🏷

Classifications

Harrison's Part

ISDS Skeletal Nosology

👪

Inheritance

1

Autosomal recessive HP:0000007

Biallelic (homozygous or compound heterozygous) pathogenic variants in CUL7, OBSL1 or CCDC8; heterozygous carriers are unaffected. Consanguinity and founder alleles are common in reported families.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:20301654 SUPPORT Human Clinical

"3-M syndrome is inherited in an autosomal recessive manner"

GeneReviews states the inheritance pattern directly.

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"If both parents are known to be heterozygous for a CCDC8, CUL7, or OBSL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants."

Defines recurrence risks conditional on both parents being carriers; this does not establish complete penetrance.

◆

Subtypes

3

3-M syndrome type 1 (CUL7-related) MONDO:0010117

CUL7 hgnc:21024

CUL7-related 3-M syndrome, the most frequently identified subtype in the initial molecular cohorts. Published series report more severe short stature on average than in OBSL1-related disease, with substantial clinical overlap. Corresponds to ISDS NOS 21-0010 and OMIM 273750.

3-M syndrome type 2 (OBSL1-related) MONDO:0013039

OBSL1 hgnc:29092

OBSL1-related 3-M syndrome, with clinical and radiographic overlap with CUL7-related disease and somewhat greater height on average in published comparisons. Corresponds to ISDS NOS 21-0020 and OMIM 612921.

3-M syndrome type 3 (CCDC8-related) MONDO:0013627

CCDC8 hgnc:25367

CCDC8-related 3-M syndrome. Few molecularly confirmed individuals have been reported, so comparative severity estimates remain uncertain. Corresponds to ISDS NOS 21-0030 and OMIM 614205.

⚙

Pathophysiology

15

Dysfunction of a 3-M Complex Component

Biallelic pathogenic variants impair CUL7, OBSL1 or CCDC8 function. CUL7 provides the scaffold of a ubiquitin ligase; OBSL1 and CCDC8 have adaptor and localization functions. Loss of either adaptor need not abolish the purified ligase catalytic activity. The experimental phenotypes below were studied in different cell types and genotypes and do not constitute one proven linear pathway.

CUL7 hgnc:21024 OBSL1 hgnc:29092 CCDC8 hgnc:25367

Animal models

OBSL1 frameshift sheep with brachygnathia, cardiomegaly and renal hypoplasia Sheep partially recapitulates A segregating predicted truncating OBSL1 variant provides a naturally occurring genetic counterpart to human OBSL1-related disease.

Downstream

Impaired Membrane Recruitment of the 3-M Complex Patient-derived variants impair membrane recruitment in cellular assays.

Reduced Cellular Response to Growth Hormone OBSL1- and CCDC8-deficient patient fibroblasts have reduced responses to GH.

Reduced Cellular Response to IGF1 CUL7- and OBSL1-deficient patient fibroblasts have reduced responses to IGF1.

Reduced IGF2 Expression Patient fibroblasts have reduced IGF2 expression; the regulatory intermediates are unresolved.

Increased H19 Expression Patient fibroblasts have increased H19 expression; the regulatory intermediates are unresolved.

Accelerated Microtubule Growth Depletion of 3-M proteins alters microtubule dynamics in studied cell lines.

Reduced Growth Plate Proliferative-zone Cellularity Cartilage-specific Cul7 deletion produces a growth-plate cellularity defect in mice.

Severe pre- and postnatal growth deficiency Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.

Relative macrocephaly Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.

Triangular face Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.

Midface retrusion Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.

Fleshy nasal tip Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.

Slender long bones Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.

Tall vertebral bodies Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.

Show evidence (4 references)

PMID:16142236 SUPPORT PRIMARY RESULT In Vitro

"CUL7 assembles an E3 ubiquitin ligase complex containing Skp1, Fbx29 (also called Fbw8) and ROC1 and promotes ubiquitination"

CUL7 assembles a ubiquitin ligase; the tested CUL7 variants impair ROC1 recruitment. These findings do not establish universal loss of catalytic activity after OBSL1 or CCDC8 dysfunction.

PMID:16142236 SUPPORT PRIMARY RESULT In Vitro

"the 3-M-associated CUL7 nonsense and missense mutations R1445X and H1464P, respectively, render CUL7 deficient in recruiting ROC1"

CUL7 assembles a ubiquitin ligase; the tested CUL7 variants impair ROC1 recruitment. These findings do not establish universal loss of catalytic activity after OBSL1 or CCDC8 dysfunction.

PMID:19481195 SUPPORT PRIMARY RESULT In Vitro

"loss of OBSL1 leads to downregulation of CUL7, implying a role for OBSL1 in the maintenance of CUL7 protein levels"

OBSL1 depletion can reduce CUL7 abundance in the studied cells.

+ 1 more reference

Impaired Membrane Recruitment of the 3-M Complex

CCDC8 phosphorylation normally promotes recruitment of OBSL1 and CUL7 to the plasma membrane. Tested patient-derived variants disrupt this localization, compromising membrane substrate targeting.

plasma membrane GO:0005886

Downstream

Reduced Cellular Ubiquitination of LL5-beta Loss of membrane recruitment is the proposed cellular basis of reduced LL5-beta ubiquitination. OBSL1 and CCDC8 are dispensable for catalysis in the purified reaction.

Show evidence (1 reference)

PMID:31343991 SUPPORT PRIMARY RESULT In Vitro

"patient-derived mutations in 3-M genes disrupted membrane localization of the 3-M complex and accumulated LL5β."

Tested patient-derived variants impair membrane localization and substrate regulation in cellular experiments.

Reduced Cellular Ubiquitination of LL5-beta

CUL7 or CCDC8 depletion reduces cellular LL5-beta polyubiquitination. This substrate-specific observation should not be generalized to loss of every ubiquitination reaction.

protein ubiquitination GO:0016567 ↓ DECREASED

Downstream

Accumulation of LL5-beta Protein Impaired ubiquitination and turnover contribute to increased LL5-beta abundance.

Show evidence (1 reference)

PMID:31343991 SUPPORT PRIMARY RESULT In Vitro

"CCDC8 promoted the polyubiquitylation of LL5β (Figure 5C), while knockdown of either CUL7 or CCDC8 reduced LL5β poly - ubiquitylation (Figure 5D)."

Cellular overexpression and knockdown assays support altered substrate ubiquitination. The full experiment coexpressed FBXW8, CUL7, OBSL1 and CCDC8.

Accumulation of LL5-beta Protein

LL5-beta, encoded by PHLDB2, accumulates after disruption of the 3-M complex. The increase in differentiated Ccdc8-null mouse trophoblast cells was not accompanied by an increase in LL5-beta gene expression.

PHLDB2 hgnc:29573

Downstream

Impaired Cell Migration LL5-beta overexpression phenocopies reduced migration in U2OS cells and supports a contribution of excess LL5-beta. The study did not establish it as the sole mediator by knockdown rescue.

Show evidence (1 reference)

PMID:31343991 SUPPORT PRIMARY RESULT In Vitro

"patient-derived mutations in 3-M genes disrupted membrane localization of the 3-M complex and accumulated LL5β."

Tested patient-derived variants impair membrane localization and substrate regulation in cellular experiments.

Impaired Cell Migration

CCDC8 depletion impairs migration and invasion in U2OS cells and mouse embryonic fibroblasts. In trophoblast cultures the migration defect is differentiation-dependent: Ccdc8-null SynT-II cells migrate less, whereas undifferentiated TSCs have migration similar to controls.

trophoblast cell migration GO:0061450 ↓ DECREASED

Downstream

Abnormal Placental Development Impaired trophoblast migration is proposed to contribute to the placental phenotype. Cultured-cell and whole-animal findings support the model without isolating migration as the only cause.

Show evidence (1 reference)

PMID:31343991 SUPPORT PRIMARY RESULT In Vitro

"Ccdc8+/+ and Ccdc8 –/– TSCs showed similar migration speed in the transwell assay, but after induction to differentiate into SynT-II cells, Ccdc8–/– cells exhibited significantly reduced migration"

Ccdc8-dependent migration was demonstrated after differentiation of mouse trophoblast stem cells into SynT-II cells, not in undifferentiated TSCs.

Abnormal Placental Development

Constitutive Ccdc8 and Cul7 mouse knockouts have abnormal placental development. A single affected human CUL7 fetus also showed abnormal chorionic villi and constricted intervillous spaces. Placental dysfunction may explain part of prenatal growth restriction; it does not by itself explain all fetal tissue abnormalities or postnatal short stature.

placenta development GO:0001890 ⚠ ABNORMAL

Animal models

Ccdc8 knockout mouse Mouse recapitulates Establishes that deleting a 3-M gene impairs trophoblast migration and placental development and produces intrauterine growth restriction.

Constitutive Cul7 (p185) knockout mouse Mouse partially recapitulates Converges on the same placental trophoblast defect from a different 3-M gene.

Downstream

Intrauterine growth restriction Mouse evidence supports a placental contribution to prenatal growth failure; its magnitude in human disease remains uncertain.

Show evidence (3 references)

PMID:31343991 SUPPORT PRIMARY RESULT Model Organism

"Deletion of Ccdc8 in mice impaired trophoblast migration and placental development, resulting in intrauterine growth restriction and perinatal lethality."

Constitutive knockout establishes the placental and fetal growth phenotypes in mice.

PMID:12904573 SUPPORT Model Organism

"placentas show defects in the differentiation of the trophoblast lineage with an abnormal vascular structure"

An independent 3-M gene knockout converges on the same placental trophoblast defect.

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"a marked increase in the number of chorionic villi with numerous syncytial knots and intervillous lacuna constriction was observed"

Placental histology from one affected 26-week CUL7 fetus, compared with an unaffected fetus; not established across all genotypes.

Reduced Cellular Response to Growth Hormone

Reduced GH-induced STAT5b and MAPK activation was found in OBSL1- and CCDC8-deficient patient fibroblasts; the assayed CUL7-deficient cells responded normally. These in vitro findings do not establish the cause of variable clinical GH treatment response.

fibroblast CL:0000057

growth hormone receptor signaling pathway GO:0060396 ↓ DECREASED

Experimental models

Patient fibroblasts for genotype-specific growth-factor responses PRIMARY CELL CULTURE Provides the gh-stimulated stat5b and mapk activation readout in patient-derived cultured cells.

Show evidence (1 reference)

PMID:23018678 SUPPORT PRIMARY RESULT In Vitro

"activation of STAT5b and MAPK in response to GH was normal in CUL7(-/-) cells but reduced in OBSL1(-/-) and CCDC8(-/-) cells compared with controls."

Patient fibroblasts show genotype-dependent GH responses; CUL7-deficient cells retained the measured response.

Reduced Cellular Response to IGF1

IGF1-induced AKT activation at five minutes was reduced in CUL7- and OBSL1-deficient patient fibroblasts, with normal responses in the assayed CCDC8-deficient cells.

fibroblast CL:0000057

insulin-like growth factor receptor signaling pathway GO:0048009 ↓ DECREASED

Experimental models

Patient fibroblasts for genotype-specific growth-factor responses PRIMARY CELL CULTURE Provides the igf1-stimulated akt activation readout in patient-derived cultured cells.

Show evidence (1 reference)

PMID:23018678 SUPPORT PRIMARY RESULT In Vitro

"Activation of AKT to IGF1 was reduced in CUL7(-/-) and OBSL1(-/-) cells at 5 min post-stimulation but normal in CCDC8(-/-) cells."

Specifies the cellular endpoint, stimulation time and genotypes tested.

Reduced IGF2 Expression

Four patient fibroblast lines representing CUL7, OBSL1 and CCDC8 genotypes showed reduced IGF2 expression compared with three controls. Assayed H19 and IGF2 methylation regions did not differ, so this finding does not establish the imprinting defect seen in Silver-Russell syndrome.

IGF2 hgnc:5466

Experimental models

Patient fibroblasts for IGF2 and H19 expression and IGF-II secretion PRIMARY CELL CULTURE Provides the igf2 rna abundance readout in patient-derived cultured cells.

Downstream

Reduced IGF-II Secretion Reduced transcript abundance accompanies reduced IGF-II secretion in the same patient fibroblast study.

Show evidence (2 references)

PMID:24148222 SUPPORT PRIMARY RESULT In Vitro

"QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."

Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three control lines.

PMID:24148222 SUPPORT PRIMARY RESULT In Vitro

"Methylation-specific PCR and pyrosequencing of the H19 ICR, H19 promotor and IGF2 DMR0 identified no differences in methylation between control and 3-M syndrome subjects, for both peripheral leucocyte and fibroblast-derived DNA."

The assayed methylation regions were unchanged; other regulatory mechanisms remain unresolved.

Increased H19 Expression

H19 expression was increased in the same four patient fibroblast lines. This is a parallel expression finding; a causal H19-to-IGF2 regulatory step was not demonstrated.

H19 hgnc:4713

Experimental models

Patient fibroblasts for IGF2 and H19 expression and IGF-II secretion PRIMARY CELL CULTURE Provides the h19 rna abundance readout in patient-derived cultured cells.

Show evidence (1 reference)

PMID:24148222 SUPPORT PRIMARY RESULT In Vitro

"QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."

Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three control lines.

Reduced IGF-II Secretion

IGF-II in conditioned medium was lower in patient than control fibroblasts. Reduced autocrine or paracrine growth stimulation is a proposed contribution to growth failure, not a demonstrated growth-plate defect in patients.

Experimental models

Patient fibroblasts for IGF2 and H19 expression and IGF-II secretion PRIMARY CELL CULTURE Provides the igf-ii in conditioned medium readout in patient-derived cultured cells.

Downstream

Severe pre- and postnatal growth deficiency The authors propose reduced local IGF-II as one explanation for growth failure; fibroblast data do not establish the mechanism in human growth plates.

Show evidence (1 reference)

PMID:24148222 SUPPORT PRIMARY RESULT In Vitro

"Levels of IGF-II secreted into conditioned cell culture medium were higher for control fibroblasts than those for 3-M fibroblasts (10.2±2.9 vs 0.6±0.9 ng/ml, P<0.01)."

Conditioned-medium ELISA documents reduced secretion in cultured patient fibroblasts.

Accelerated Microtubule Growth

Loss of 3-M proteins accelerates microtubule growth in experimental cell lines. Effects depend on cell context and expression; this branch is not asserted to be downstream of membrane localization or LL5-beta accumulation.

microtubule cytoskeleton organization GO:0000226 ⚠ ABNORMAL

Downstream

Delayed Mitotic Progression The study links altered microtubule dynamics to chromosome congression defects and mitotic delay.

Defective Cytokinesis Microtubule abnormalities and cytokinesis failure occur after CUL7 depletion; the complete causal sequence remains unresolved.

Show evidence (1 reference)

PMID:24793695 SUPPORT PRIMARY RESULT In Vitro

"First, loss of 3M proteins accelerates microtubule growth in both interphase and mitotic cells, implying a function for the 3M complex in either inhibiting microtubule growth or promoting microtubule catastrophe."

Cell depletion experiments directly measured altered microtubule dynamics.

Delayed Mitotic Progression

CUL7 depletion delays chromosome congression and mitotic progression in cultured cells. Spindle-checkpoint manipulation can remove the delay without demonstrating restoration of chromosome segregation fidelity.

mitotic cell cycle GO:0000278 ⚠ ABNORMAL

Show evidence (1 reference)

PMID:24793695 SUPPORT PRIMARY RESULT In Vitro

"Together, these results indicated that CUL7 depletion delayed mitotic progression due to impaired chromosome congression at prometaphase and also causes defects in cytokinesis."

Live-cell experiments demonstrate both mitotic delay and cytokinesis defects after CUL7 depletion.

Defective Cytokinesis

CUL7 depletion causes cytokinesis defects and increased ploidy. Two CUL7-mutant patient fibroblast lines also showed increased ploidy. Wild-type CUL7 rescue was demonstrated in CUL7-depleted experimental cells, not in patient fibroblasts.

cytokinesis GO:0000910 ⚠ ABNORMAL

Experimental models

CUL7-mutant patient fibroblasts for ploidy assessment PRIMARY CELL CULTURE Provides the tetraploid-cell proportion readout in patient-derived cultured cells.

Show evidence (2 references)

PMID:24793695 SUPPORT PRIMARY RESULT In Vitro

"Together, these results indicated that CUL7 depletion delayed mitotic progression due to impaired chromosome congression at prometaphase and also causes defects in cytokinesis."

Live-cell experiments demonstrate both mitotic delay and cytokinesis defects after CUL7 depletion.

PMID:24793695 SUPPORT PRIMARY RESULT In Vitro

"Ectopic expression of wild-type CUL7 effectively rescued the defects in CUL7 depleted cells, reducing the tetraploid/polyploid cells to 5.2%."

Rescue experiment in CUL7-depleted cells supports the specificity of the observed cellular defect.

Reduced Growth Plate Proliferative-zone Cellularity

Cartilage-specific Cul7 knockout mice have fewer cells in the growth-plate proliferative zone, disorganized chondrocyte columns, altered matrix and short deformed limbs. The comparator was Cul7fl/+;Col2a1-CreERT2. This supports a tissue-specific skeletal role for CUL7, without proving a proliferation-rate defect, an upstream GH/IGF cause, or equivalent effects of OBSL1 and CCDC8.

chondrocyte CL:0000138

Animal models

Cartilage-specific Cul7 knockout mouse Mouse recapitulates Models reduced proliferative-zone cellularity and abnormal skeletal growth after cartilage-specific Cul7 deletion.

Downstream

Severe pre- and postnatal growth deficiency The mouse cartilage phenotype supports a possible contribution to skeletal growth failure; human prenatal growth and non-skeletal features require additional explanations.

Show evidence (1 reference)

PMID:38367951 SUPPORT PRIMARY RESULT Model Organism

"decreased number of cells in the proliferation zone"

Histological cell number is reduced in cartilage-specific Cul7 knockout mice; this is not a direct proliferation-rate measurement.

✶

Histopathology

2

Reduced bronchial cartilaginous lamina

In one affected 26-week CUL7 fetus, compared with an unaffected fetus, medium and large bronchi had small, insufficiently developed cartilaginous laminae. Alveolar tissues showed no obvious abnormality. This observation supports a possible airway-development contribution to neonatal respiratory distress without establishing a universal mechanism.

Show evidence (1 reference)

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"the amount of cartilaginous lamina of the medium and large bronchi was small and the cartilaginous lamina insufficiently developed"

Single affected fetal specimen; frequency and causal contribution to liveborn respiratory distress remain uncertain.

Abnormal chorionic villi and intervillous spaces

The same affected fetal placenta had increased chorionic villi with numerous syncytial knots and constricted intervillous lacunae. Trophoblast giant-cell number was normal, contrasting with aspects of the constitutive mouse knockout phenotype.

Show evidence (1 reference)

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"a marked increase in the number of chorionic villi with numerous syncytial knots and intervillous lacuna constriction was observed"

Human fetal histology provides a limited clinical counterpart to the mouse placental models.

⬡

Pathograph

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Phenotypes

59

Digestive 3

Protuberant abdomen HP:0001538

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Protuberant abdomen | 30/35 | 86% | 22/27 | 81% | 0/1 | NA |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Hepatomegaly HP:0002240

Show evidence (1 reference)

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"Hepatomegaly | 5 (20) | 0 | 0 | 0 | 5 (12)"

Table 2 gives age-group counts followed by the total count and percentage in the 43-person founder cohort.

Diastasis recti HP:0001540

Show evidence (1 reference)

PMID:41437277 SUPPORT PRIMARY RESULT Human Clinical

"The examination showed a slightly protuberant abdomen with diastasis recti."

Individual longitudinal case observation; no general frequency inferred.

Ear 2

Protruding ears HP:0000411

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Prominent ears | 35/53 | 66% | 23/37 | 62% | 5/9 | 56% |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Dysplastic ears Abnormal pinna morphology HP:0000377

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"Dysplasia of ears | 11 (40) | 4 (50) | 5 (100) | 0 | 20 (47)"

Table 2 gives age-group counts followed by the total count and percentage in the 43-person founder cohort.

Endocrine 2

Hypogonadism in males HP:0000135

Show evidence (3 references)

PMID:20301654 SUPPORT Human Clinical

"Males with 3-M syndrome can have hypogonadism and occasionally hypospadias."

GeneReviews records hypogonadism as a male-restricted feature.

PMID:40974508 SUPPORT PRIMARY RESULT Human Clinical

"Pubertal arrest was noted in seven male patients, while two female siblings and one male patient experienced rapidly progressive puberty."

Recent retrospective cohort documents variable pubertal trajectories; the abstract does not provide a denominator restricted to pubertally assessable males.

PMID:38847008 SUPPORT PRIMARY RESULT Human Clinical

"Subsequently, a regression of testicular volumes, increased gonadotropin levels, and reduced (although normal) testosterone levels were observed."

A CUL7-related case developed gonadal dysfunction after spontaneous pubertal progression; hormone and testicular findings support longitudinal endocrine monitoring.

Growth hormone deficiency Decreased response to growth hormone stimulation test HP:0000824

Show evidence (1 reference)

PMID:23517720 SUPPORT PRIMARY RESULT Human Clinical

"The patient also exhibited severe GHD (GH <5 ng/ml) and from the age of 18 months was treated with rhGH."

Single molecularly confirmed patient; refutes an absolute exclusion of GH deficiency.

Eye 1

Hypertelorism HP:0000316

Show evidence (1 reference)

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"Hypertelorism | 9 (36) | 4 (50) | 1 (20) | 5 (100) | 19 (44)"

Table 2 gives age-group counts followed by the total count and percentage in the 43-person founder cohort.

Genitourinary 1

Hypospadias OCCASIONAL HP:0000047

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"Males with 3-M syndrome can have hypogonadism and occasionally hypospadias."

GeneReviews records hypospadias as an occasional male finding.

Head and Neck 16

Relative macrocephaly HP:0004482

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"

GeneReviews lists relative macrocephaly among the characteristic facial features.

Triangular face HP:0000325

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"

Listed by GeneReviews among the characteristic facial features.

Dolichocephaly HP:0000268

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"

Listed by GeneReviews among the characteristic facial features.

Midface retrusion HP:0011800

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"

Listed by GeneReviews among the characteristic facial features.

Fleshy nasal tip Bulbous nose HP:0000414

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"

Listed by GeneReviews among the characteristic facial features.

Thick eyebrows HP:0000574

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"thick eyebrows, fleshy nasal tip, long philtrum"

Listed by GeneReviews among the characteristic facial features.

Long philtrum HP:0000343

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"thick eyebrows, fleshy nasal tip, long philtrum"

Listed by GeneReviews among the characteristic facial features.

Pointed chin HP:0000307

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"thick vermilion of the upper and low lips, and pointed chin"

Listed by GeneReviews among the characteristic facial features.

Short neck HP:0000470

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"Additional features of 3-M syndrome include short, broad neck, prominent trapezii"

Listed by GeneReviews among the additional skeletal features.

Frontal bossing HP:0002007

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Frontal bossing | 76/90 | 84% | 46/59 | 78% | 11/12 | 92% |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Anteverted nares HP:0000463

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Anteverted nares | 58/63 | 92% | 35/44 | 80% | 8/12 | 67% |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Thick upper lip vermilion HP:0000215

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"thick vermilion of the upper and low lips"

GeneReviews explicitly describes involvement of both lips.

Thick lower lip vermilion HP:0000179

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"thick vermilion of the upper and low lips"

GeneReviews explicitly describes involvement of both lips.

Broad neck HP:0000475

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"Additional features of 3-M syndrome include short, broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or distal joint..."

GeneReviews lists this feature.

Epicanthus HP:0000286

Show evidence (1 reference)

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"Epicanthus | 14 (56) | 1 (12) | 2 (40) | 0 | 17 (40)"

Table 2 gives age-group counts followed by the total count and percentage in the 43-person founder cohort.

Depressed nasal bridge HP:0005280

Show evidence (1 reference)

PMID:41437277 SUPPORT PRIMARY RESULT Human Clinical

"On physical examination, he had slightly depressed nasal bridge, bulbous nasal tip pointing upwards, slightly pointed chin, bilateral brachydactyly, and single transverse palmar crease on the right hand."

Findings in patient 1 at age 12 years.

Integument 1

Single transverse palmar crease HP:0000954

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Unique transverse palmar crease | 14/22 | 64% | 2/9 | 22% | 0/0 | NA |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Limbs 10

Winged scapulae Scapular winging HP:0003691

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae"

Listed by GeneReviews among the additional skeletal features.

Clinodactyly of the fifth fingers Clinodactyly of the 5th finger HP:0004209

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips"

Listed by GeneReviews among the additional skeletal features.

Dislocated hips Hip dislocation HP:0002827

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips"

Listed by GeneReviews among the additional skeletal features.

Prominent heels Prominent calcaneus HP:0012428

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"dislocated hips, prominent heels, and pes planus"

Listed by GeneReviews among the additional skeletal features.

Pes planus HP:0001763

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"dislocated hips, prominent heels, and pes planus"

Listed by GeneReviews among the additional skeletal features.

Flared metaphyses Flared metaphysis HP:0003015

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Flared metaphyses | 30/33 | 91% | 17/23 | 74% | 1/1 | NA |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Diaphyseal constriction Slender long bones with narrow diaphyses HP:0004993

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Diaphyseal constriction | 37/43 | 86% | 24/28 | 86% | 1/1 | NA |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Brachydactyly HP:0001156

Show evidence (1 reference)

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"A short neck, short and wide thorax, brachydactyly, micromelia of the hands and feet and prominent heels were observed in >95% of the patients in all generations"

Describes the high prevalence of these features within this specific founder cohort.

Small hands HP:0200055

Show evidence (1 reference)

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"A short neck, short and wide thorax, brachydactyly, micromelia of the hands and feet and prominent heels were observed in >95% of the patients in all generations"

Describes the high prevalence of these features within this specific founder cohort.

Short feet Short foot HP:0001773

Show evidence (1 reference)

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"A short neck, short and wide thorax, brachydactyly, micromelia of the hands and feet and prominent heels were observed in >95% of the patients in all generations"

Describes the high prevalence of these features within this specific founder cohort.

Musculoskeletal 12

Slender long bones HP:0003100

Show evidence (2 references)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Slender long bones | 57/72 | 79% | 41/51 | 80% | 7/11 | 64% |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"Notably, the characteristic radiological findings for 3‐M syndrome(slender tubular bones or tall vertebral bodies) were observed in few patients"

The Yakut CUL7 founder cohort illustrates population-associated radiographic variability.

Tall vertebral bodies Increased vertebral height HP:0004570

Show evidence (2 references)

PMID:41437277 SUPPORT Human Clinical

"3-M syndrome (OMIM# 273750, 612921, 614205) is a rare autosomal recessive disease characterized by severe pre- and post-natal growth retardation, bulbous nose, short thorax, prominent abdomen, slight slender tubular bones, tall vertebral bodies, and normal intelligence."

Names tall vertebral bodies among the defining features of the disorder.

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Tall vertebral bodies | 45/71 | 63% | 33/50 | 66% | 5/11 | 45% |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Short thorax HP:0010306

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae"

Listed by GeneReviews among the additional skeletal features.

Pectus carinatum HP:0000768

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae"

GeneReviews records pectus carinatum or excavatum; carinatum is bound here and excavatum is curated as its own phenotype.

Pectus excavatum HP:0000767

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae"

The alternative chest-wall deformity recorded by GeneReviews.

Thoracic kyphoscoliosis HP:0002751

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta"

Listed by GeneReviews among the additional skeletal features.

Hyperlordosis HP:0003307

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta"

Listed by GeneReviews among the additional skeletal features.

Joint hypermobility HP:0001382

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips"

Listed by GeneReviews among the additional skeletal features.

Squared-off shoulders HP:6000464

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Squared-off shoulders | 28/35 | 80% | 16/23 | 70% | 3/7 | 43% |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Scoliosis | 11/62 | 18% | 13/48 | 27% | 2/12 | 17% |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"Muscular hypotonia | 25 (100) | 7 (88) | 5 (100) | 0 | 37 (86)"

Table 2 gives age-group counts followed by the total count and percentage in the 43-person founder cohort.

Delayed bone age Delayed skeletal maturation HP:0002750

Show evidence (1 reference)

PMID:40974508 SUPPORT PRIMARY RESULT Human Clinical

"Dysmorphic features characteristic of 3-M syndrome and delayed bone age were observed in all patients."

Retrospective cohort of 24 genetically confirmed patients.

Nervous System 3

Spina bifida occulta HP:0003298

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta"

Listed by GeneReviews among the additional skeletal features.

Psychomotor developmental delay Neurodevelopmental delay HP:0012758

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Psychomotor delay | 8/45 | 18% | 5/25 | 20% | 1/5 | 20% |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"It should be noted that only patients with variants in OBSL1 presented with intellectual disability, while the majority of patients with CUL7- or CCDC8-related 3-M syndrome and available neuropsychological assessment data had normal intellect."

Genotype distribution in the reviewed reports; normal intellect was recorded in 20/22 OBSL1 cases with relevant data.

Respiratory 1

Neonatal respiratory distress HP:0002643

Show evidence (1 reference)

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"In total, 18 (41.9%) infants had severe asphyxia and respiratory distress at birth and 11 (25.6%) infants required mechanical ventilation."

Clinical observation in the 43-person Yakut founder cohort.

Growth 2

Severe pre- and postnatal growth deficiency VERY_FREQUENT Short stature HP:0004322

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"3-M syndrome is characterized by severe pre- and postnatal growth deficiency (final height five standard deviations below the mean)"

The defining feature, quantified by GeneReviews.

Intrauterine growth restriction VERY_FREQUENT Intrauterine growth retardation HP:0001511

Show evidence (1 reference)

PMID:19481195 SUPPORT Human Clinical

"3-M syndrome is an autosomal-recessive primordial growth disorder characterized by significant intrauterine and postnatal growth restriction"

Prenatal onset is what makes 3-M a primordial rather than a postnatal growth disorder.

Other 5

Midline facial vascular mark

Needs term/NTR: no precise HPO binding was identified for this source-specific vascular mark. It is not assumed to be an infantile vascular tumor or a port-wine stain. OLS4 hp search q="midline facial haemangioma" (2026-09-21) returned no results.

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Midline facial haemangioma | 11/37 | 30% | 6/32 | 19% | 2/5 | 40% |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Lower eyelid fat pads

Needs term/NTR: no precise HPO binding was identified for lower eyelid fat pads. This finding is not equated with eyelid edema. OLS4 hp search q="lower eyelid fat pads" (2026-09-21) returned Blepharochalasis (HP:0010749), which does not denote lower eyelid fat pads.

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Lower eyelid fat pads | 18/54 | 33% | 13/41 | 32% | 0/6 | 0% |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Prominent central tubercle of the upper lip

Needs term/NTR: no precise HPO binding was identified for this finding. OLS4 hp search q="prominent central tubercle upper lip" (2026-09-21) returned no results.

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Prominent central tubercle of upper lip | 21/37 | 57% | 17/23 | 74% | 2/5 | 40% |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Transverse chest groove

Needs term/NTR: no precise HPO binding was identified for this finding. OLS4 hp search q="transverse chest groove" (2026-09-21) returned no results.

Show evidence (1 reference)

PMID:41437277 SUPPORT REVIEW SYNTHESIS Human Clinical

"| Chest groove | 14/27 | 52% | 12/25 | 48% | 2/7 | 29% |"

Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not population frequencies.

Prominent trapezius muscles

Needs term/NTR: retained as a specific unbound finding rather than equated with muscle hypertrophy. OLS4 hp search q="prominent trapezius" (2026-09-21) returned no results.

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"Additional features of 3-M syndrome include short, broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or distal joint..."

GeneReviews lists this feature.

🧬

Genetic Associations

3

CUL7

Gene: CUL7 hgnc:21024 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:16142236 SUPPORT In Vitro

"Functional studies indicated that the 3-M-associated CUL7 nonsense and missense mutations R1445X and H1464P, respectively, render CUL7 deficient in recruiting ROC1."

The discovery study links patient-associated CUL7 variants to impaired ROC1 recruitment in functional assays.

OBSL1

Gene: OBSL1 hgnc:29092 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:19481195 SUPPORT Human Clinical

"we subsequently discovered seven distinct null mutations from 10 families within the gene OBSL1"

The locus-mapping and mutation study that established OBSL1 as the second 3-M gene.

CCDC8

Gene: CCDC8 hgnc:25367 relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:21737058 SUPPORT Human Clinical

"Exome sequencing now identifies mutations in CCDC8 as a cause of 3-M syndrome."

The exome study that established CCDC8 as the third 3-M gene.

💊

Medical Actions

11

Growth Hormone Therapy

Action: Pharmacotherapy NCIT:C15986

Agent: somatropin NCIT:C837

Platform: Protein replacement

Pediatric endocrine assessment can guide consideration of recombinant GH in prepubertal children. Response varies, and GH deficiency can coexist. A retrospective 24-patient series treated 13 children for one to seven years: seven had a favorable response and the median height-SDS change was +0.3, with a range of -0.8 to +2.3. These uncontrolled data do not establish uniform benefit or its mechanism.

Target Phenotypes: Short stature HP:0004322

Show evidence (3 references)

PMID:20301654 SUPPORT Human Clinical

"Referral to pediatric endocrinologist for consideration of growth hormone in prepubertal children."

GeneReviews management recommendation.

PMID:23018678 SUPPORT Human Clinical

"3-M patients typically have a modest response to GH treatment, but the mechanism is unknown."

The source explicitly states that the mechanism underlying the typically modest response is unknown.

PMID:40974508 SUPPORT PRIMARY RESULT Human Clinical

"The overall median change in height SDS was +0.3 (–0.8 to +2.3), reflecting variability in response among patients receiving treatment. A favorable response was observed in 7 out of 13 patients (54%)."

Retrospective treated subset; no randomized comparator and no uniform efficacy assumption.

Orthopedic management

Orthopedic evaluation guides management of hip dislocation, scoliosis and significant joint laxity; evaluation itself does not imply surgery.

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"Orthopedic evaluation in individuals with hip dislocation, scoliosis, and significant joint laxity is essential."

GeneReviews management recommendation.

Surgical limb lengthening

Action: Orthopedic Surgical Procedure NCIT:C16186

Platform: Surgery

Limb lengthening may be considered as an option after specialist assessment; the cited synthesis does not provide controlled efficacy or complication estimates.

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"Surgical limb lengthening may also be an option."

GeneReviews management recommendation.

Physical therapy

Action: Physical Therapy NCIT:C15302

Physical therapy supports mobility and adaptations for short stature.

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"Physical therapy, occupational therapy, and community child health services are important in ensuring necessary adaptations for short stature are put in place to maximize access to the individual's environment."

GeneReviews management recommendation.

Occupational therapy

Action: Occupational Therapy NCIT:C121351

Occupational therapy and community child-health services support access to the environment and daily activities.

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"Physical therapy, occupational therapy, and community child health services are important in ensuring necessary adaptations for short stature are put in place to maximize access to the individual's environment."

GeneReviews management recommendation.

Endocrine management of hypogonadism

Monitor pubertal progression and refer gonadal dysfunction to endocrinology; spontaneous pubertal onset does not exclude later arrest.

Show evidence (2 references)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"Management of hypogonadism per endocrinologist."

GeneReviews management recommendation.

PMID:38847008 SUPPORT PRIMARY RESULT Human Clinical

"Subsequently, a regression of testicular volumes, increased gonadotropin levels, and reduced (although normal) testosterone levels were observed."

A CUL7-related case developed gonadal dysfunction after spontaneous pubertal progression; hormone and testicular findings support longitudinal endocrine monitoring.

Urologic management of hypospadias

Urology referral may be needed for hypospadias, with care adapted to the individual anatomy.

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"Urology referral may be needed for hypospadias."

GeneReviews management recommendation.

Neonatal respiratory support

Severe neonatal respiratory distress requires neonatal or pediatric intensive-care input and subsequent respiratory follow-up.

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"In neonates with severe respiratory distress, neonatal/pediatric intensive care team input and follow up with a pediatric respiratory physician."

GeneReviews management recommendation.

Pregnancy care

Pregnancy care should follow guidance for women with dwarfism or small stature, with attention to premature birth risk.

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"Follow pregnancy management guidelines as for women with other forms of dwarfism or small stature to reduce the risk of premature birth."

GeneReviews management recommendation.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Autosomal recessive counseling: a 25% recurrence risk for each sib once both parents are known carriers, with carrier testing and prenatal or preimplantation genetic testing possible after the familial variants are identified.

Show evidence (2 references)

PMID:20301654 SUPPORT Human Clinical

"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier"

GeneReviews genetic counseling guidance.

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"Once the 3-M syndrome-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."

Defines prerequisites for reproductive and family testing.

Recombinant IGF1 therapy, investigational reported use

Action: Pharmacotherapy NCIT:C15986

Agent: Mecasermin NCIT:C2262

A single CUL7-related case received recombinant IGF1 for presumed GH insensitivity. Height improvement was minimal and accelerated weight gain, morbid obesity and associated complications developed; therapy was discontinued. This report does not support routine use.

Show evidence (1 reference)

PMID:32924381 SUPPORT PRIMARY RESULT Human Clinical

"This case highlights the novel use of rhIGF-1 therapy on a child with 3-M syndrome-1 with minimal height benefit but accelerated weight gain"

Single-patient experience with limited benefit and adverse outcomes; not a recommendation.

🔬

Diagnosis

6

Molecular genetic testing of CUL7, OBSL1 and CCDC8 (Biallelic pathogenic variants in CUL7, OBSL1 or CCDC8)

Diagnosis can be established by the characteristic prenatal-onset persistent growth deficiency with clinical and radiographic features and/or biallelic pathogenic variants in CUL7, OBSL1 or CCDC8. Molecular testing distinguishes overlapping growth disorders and assigns the subtype.

molecular genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:20301654 SUPPORT Human Clinical

"The diagnosis of 3-M syndrome is established in a proband with prenatal-onset persistent growth deficiency and the characteristic clinical and radiographic features and/or biallelic pathogenic variants in CCDC8, CUL7, or OBSL1 identified by molecular genetic testing."

The GeneReviews diagnostic criterion, naming both the clinical route and the three genes.

Skeletal radiography (Slender long bones with tall vertebral bodies, on a background of prenatal-onset growth deficiency)

Skeletal radiography can identify slender long bones and tall vertebral bodies with reduced anteroposterior dimensions. Expression varies with genotype and age: some findings become more evident during childhood, whereas other clinical features become less distinctive. Absence of the classic radiographic pattern should be interpreted with the clinical and molecular findings.

Skeletal radiography NCIT:C128940

Show evidence (3 references)

PMID:11665997 SUPPORT Human Clinical

"3-M syndrome can be differentiated from other types of dwarfism by clinical criteria and by the demonstration of characteristically slender long bones and foreshortened vertebral bodies."

States the differentiating radiographic findings.

PMID:41437277 SUPPORT Human Clinical

"Our paper highlights how the clinical diagnosis of 3-M is easier in the first months of life, while in older children the phenotype becomes increasingly nuanced."

The age-dependence caveat, which is why molecular testing carries more of the diagnostic weight in an older child.

PMID:23517720 SUPPORT PRIMARY RESULT Human Clinical

"Then, during childhood tall vertebral bodies, hip dislocation, transverse chest groove, winged scapulae and hyperextensible joints became more evident and the diagnosis of 3-M syndrome was made"

Longitudinal case demonstrates that skeletal findings can emerge or become more evident during childhood.

Growth surveillance

Record growth and growth velocity every six to twelve months using standard growth charts.

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"Monitor growth every six to 12 months on standard growth charts, with special attention to growth velocity."

GeneReviews surveillance or family-evaluation recommendation.

Musculoskeletal surveillance

Assess joint hypermobility and kyphoscoliosis annually, and hip dislocation at each infant visit, particularly with delayed walking.

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"Assess for joint hypermobility and kyphoscoliosis annually. Assess for hip dislocation at each visit in infancy especially in those with delayed walking."

GeneReviews surveillance or family-evaluation recommendation.

Adolescent aortic root assessment

Consider echocardiography in adolescence to assess aortic root diameter. This is a surveillance recommendation, not evidence that aortic disease is universal.

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"Consider echocardiogram in adolescence to evaluate aortic root diameter."

GeneReviews surveillance or family-evaluation recommendation.

Evaluation of siblings at risk

Evaluate siblings for short stature and consider 3-M syndrome when present. Familial variant testing informs diagnosis and counseling.

Show evidence (1 reference)

PMID:20301654 SUPPORT REVIEW SYNTHESIS Human Clinical

"It is appropriate to evaluate sibs of a proband for short stature and, if present, 3-M syndrome to ensure a correct diagnosis is made in affected sibs."

GeneReviews surveillance or family-evaluation recommendation.

📊

Prevalence

2

Worldwide

Cases In Literature Not yet documented

A worldwide population rate is not established. Published cohorts are clinically ascertained and founder populations should be considered separately.

Yakut population, historical 2007 estimate

Point Prevalence 10 per 100,000 1–9 per 10,000 3M1

The authors estimated approximately 0.01%, based on at least 43 affected people. The normalized rate is approximate and should not be extrapolated worldwide.

Show evidence (1 reference)

PMID:17675530 SUPPORT PRIMARY RESULT Human Clinical

"The prevalence rate of short stature syndrome with CUL7 mutation in Yakut is ∼0.01% (at least 43 patients among 440 000 people)"

Population-specific historical estimate for a CUL7 founder-variant cohort.

🧫

Experimental Models

3

Patient fibroblasts for genotype-specific growth-factor responses PRIMARY_CELL_CULTURE

Patient-derived fibroblasts representing CUL7, OBSL1 and CCDC8 defects were used to compare GH- and IGF1-stimulated intracellular signaling. The observed response depends on the mutated gene and the assayed pathway.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Patient-derived skin fibroblasts with molecularly confirmed 3-M syndrome

Culture

Cultured fibroblast monolayers

Publication

PMID:23018678

Pathograph links

Reduced Cellular Response to Growth Hormone measures fidelity: moderate Provides the gh-stimulated stat5b and mapk activation readout in patient-derived cultured cells.

Limitations: Response differs by genotype: OBSL1 and CCDC8 cells had reduced GH responses, whereas CUL7 and OBSL1 cells had reduced early IGF1 responses. These assays do not establish the cause of variable clinical GH efficacy.

Readouts

GH-stimulated STAT5b and MAPK activation

Direction: DECREASED

Interpretation: Cellular measurement under the study conditions; it does not directly establish human growth-plate physiology.

Show evidence (1 reference)

PMID:23018678 SUPPORT PRIMARY RESULT In Vitro

"activation of STAT5b and MAPK in response to GH was normal in CUL7(-/-) cells but reduced in OBSL1(-/-) and CCDC8(-/-) cells compared with controls."

Patient fibroblasts show genotype-dependent GH responses; CUL7-deficient cells retained the measured response.

Show evidence (1 reference)

PMID:23018678 SUPPORT PRIMARY RESULT In Vitro

"activation of STAT5b and MAPK in response to GH was normal in CUL7(-/-) cells but reduced in OBSL1(-/-) and CCDC8(-/-) cells compared with controls."

Patient fibroblasts show genotype-dependent GH responses; CUL7-deficient cells retained the measured response.

Reduced Cellular Response to IGF1 measures fidelity: moderate Provides the igf1-stimulated akt activation readout in patient-derived cultured cells.

Limitations: Response differs by genotype: OBSL1 and CCDC8 cells had reduced GH responses, whereas CUL7 and OBSL1 cells had reduced early IGF1 responses. These assays do not establish the cause of variable clinical GH efficacy.

Readouts

IGF1-stimulated AKT activation

Direction: DECREASED

Interpretation: Cellular measurement under the study conditions; it does not directly establish human growth-plate physiology.

Show evidence (1 reference)

PMID:23018678 SUPPORT PRIMARY RESULT In Vitro

"Activation of AKT to IGF1 was reduced in CUL7(-/-) and OBSL1(-/-) cells at 5 min post-stimulation but normal in CCDC8(-/-) cells."

Specifies the cellular endpoint, stimulation time and genotypes tested.

Show evidence (1 reference)

PMID:23018678 SUPPORT PRIMARY RESULT In Vitro

"Activation of AKT to IGF1 was reduced in CUL7(-/-) and OBSL1(-/-) cells at 5 min post-stimulation but normal in CCDC8(-/-) cells."

Specifies the cellular endpoint, stimulation time and genotypes tested.

Patient fibroblasts for IGF2 and H19 expression and IGF-II secretion PRIMARY_CELL_CULTURE

Forearm fibroblasts from four prepubertal patients, one with CUL7, two with OBSL1 and one with CCDC8 variants, were compared with three control lines derived from skin tags. Quantitative PCR measured RNA abundance and ELISA measured IGF-II in conditioned medium. Assayed H19 and IGF2 methylation regions did not differ.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Patient-derived skin fibroblasts with molecularly confirmed 3-M syndrome

Culture

Cultured fibroblast monolayers

Publication

PMID:24148222

Pathograph links

Reduced IGF2 Expression measures fidelity: moderate Provides the igf2 rna abundance readout in patient-derived cultured cells.

Limitations: Four patient lines were compared with three controls. Cultured skin fibroblasts do not directly model placental or growth-plate tissue, and no causal rescue of human growth was demonstrated.

Readouts

IGF2 RNA abundance

Direction: DECREASED

Interpretation: Cellular measurement under the study conditions; it does not directly establish human growth-plate physiology.

Show evidence (1 reference)

PMID:24148222 SUPPORT PRIMARY RESULT In Vitro

"QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."

Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three control lines.

Show evidence (1 reference)

PMID:24148222 SUPPORT PRIMARY RESULT In Vitro

"QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."

Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three control lines.

Increased H19 Expression measures fidelity: moderate Provides the h19 rna abundance readout in patient-derived cultured cells.

Limitations: Four patient lines were compared with three controls. Cultured skin fibroblasts do not directly model placental or growth-plate tissue, and no causal rescue of human growth was demonstrated.

Readouts

H19 RNA abundance

Direction: INCREASED

Interpretation: Cellular measurement under the study conditions; it does not directly establish human growth-plate physiology.

Show evidence (1 reference)

PMID:24148222 SUPPORT PRIMARY RESULT In Vitro

"QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."

Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three control lines.

Show evidence (1 reference)

PMID:24148222 SUPPORT PRIMARY RESULT In Vitro

"QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."

Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three control lines.

Reduced IGF-II Secretion measures fidelity: moderate Provides the igf-ii in conditioned medium readout in patient-derived cultured cells.

Limitations: Four patient lines were compared with three controls. Cultured skin fibroblasts do not directly model placental or growth-plate tissue, and no causal rescue of human growth was demonstrated.

Readouts

IGF-II in conditioned medium

Direction: DECREASED

Interpretation: Cellular measurement under the study conditions; it does not directly establish human growth-plate physiology.

Show evidence (1 reference)

PMID:24148222 SUPPORT PRIMARY RESULT In Vitro

"Levels of IGF-II secreted into conditioned cell culture medium were higher for control fibroblasts than those for 3-M fibroblasts (10.2±2.9 vs 0.6±0.9 ng/ml, P<0.01)."

Conditioned-medium ELISA documents reduced secretion in cultured patient fibroblasts.

Show evidence (1 reference)

PMID:24148222 SUPPORT PRIMARY RESULT In Vitro

"Levels of IGF-II secreted into conditioned cell culture medium were higher for control fibroblasts than those for 3-M fibroblasts (10.2±2.9 vs 0.6±0.9 ng/ml, P<0.01)."

Conditioned-medium ELISA documents reduced secretion in cultured patient fibroblasts.

Show evidence (1 reference)

PMID:24148222 SUPPORT PRIMARY RESULT In Vitro

"Skin fibroblast cell lines were derived from four 3-M syndrome patients and three control subjects."

The Methods specify the biological sampling units; technical replicate wells are not additional patients.

CUL7-mutant patient fibroblasts for ploidy assessment PRIMARY_CELL_CULTURE

Two patient skin fibroblast lines carrying CUL7 variants were compared with normal foreskin and lung fibroblast cell lines. Increased ploidy provided a patient-derived correlate of cell-division defects studied separately in depleted experimental cell lines.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Patient-derived skin fibroblasts with molecularly confirmed 3-M syndrome

Culture

Cultured fibroblast monolayers

Publication

PMID:24793695

Pathograph links

Defective Cytokinesis measures fidelity: moderate Provides the tetraploid-cell proportion readout in patient-derived cultured cells.

Limitations: Ploidy is an indirect correlate of cell-division failure. The comparator lines differ in tissue source and passage, and the reported wild-type CUL7 rescue was performed in CUL7-depleted experimental cells rather than these patient fibroblasts.

Readouts

Tetraploid-cell proportion

Direction: INCREASED

Interpretation: Cellular measurement under the study conditions; it does not directly establish human growth-plate physiology.

Show evidence (1 reference)

PMID:24793695 SUPPORT PRIMARY RESULT In Vitro

"These two lines of 3M fibroblast cells contained 8.8% and 6.4% of tetraploid cells"

Patient-line ploidy measurement. Control cell lines differed in tissue origin and passage; the result is not a direct live-cell assay of cytokinesis in patients.

Show evidence (1 reference)

PMID:24793695 SUPPORT PRIMARY RESULT In Vitro

"These two lines of 3M fibroblast cells contained 8.8% and 6.4% of tetraploid cells"

Patient-line ploidy measurement. Control cell lines differed in tissue origin and passage; the result is not a direct live-cell assay of cytokinesis in patients.

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Animal Models

4

Cartilage-specific Cul7 knockout mouse

A conditional, cartilage-restricted Cul7 knockout that survives past birth, unlike the constitutive null, and so allows the growth plate to be studied directly.

Species

Mouse

Genotype

Cul7fl/fl;Col2a1-CreERT2

Publication

PMID:38367951

Pathograph links

Reduced Growth Plate Proliferative-zone Cellularity recapitulates fidelity: moderate Models reduced proliferative-zone cellularity and abnormal skeletal growth after cartilage-specific Cul7 deletion.

Limitations: Conditional, tissue-restricted CUL7 knockout, compared with Cul7fl/+;Col2a1-CreERT2 mice. It does not establish human growth-plate histology, a direct proliferation-rate defect, or equivalent mechanisms for OBSL1 and CCDC8.

Readouts

Proliferative-zone chondrocyte number

Direction: DECREASED

Interpretation: Histological cell count, rather than a directly assayed proliferation rate.

Show evidence (1 reference)

PMID:38367951 SUPPORT Model Organism

"decreased number of cells in the proliferation zone"

The measured reduction in proliferative-zone cellularity.

Limb length

Direction: DECREASED

Interpretation: Associated skeletal-growth phenotype after cartilage-specific Cul7 deletion.

Show evidence (1 reference)

PMID:38367951 SUPPORT Model Organism

"mice had abnormally short and deformed limbs"

The gross skeletal readout of the model.

Show evidence (1 reference)

PMID:38367951 SUPPORT Model Organism

"The knockout of Cul7 gene may affect both the proliferation of chondrocytes and the endochondral osteogenesis"

Supports treating this model as informative for the growth-plate node.

Ccdc8 knockout mouse

Constitutive Ccdc8 deletion produces placental abnormalities together with intrauterine growth restriction; additional fetal tissue defects may contribute.

Species

Mouse

Genotype

Ccdc8 null

Publication

PMID:31343991

Pathograph links

Abnormal Placental Development recapitulates fidelity: moderate Establishes that deleting a 3-M gene impairs trophoblast migration and placental development and produces intrauterine growth restriction.

Limitations: Constitutive deletion causes perinatal lethality in mice, whereas human CCDC8-related disease permits survival into adulthood. The model cannot directly address human postnatal growth or establish relative severity among human genotypes.

Readouts

Fetal growth

Direction: DECREASED

Interpretation: Fetal growth restriction accompanying placental abnormalities in the knockout.

Show evidence (1 reference)

PMID:31343991 SUPPORT Model Organism

"resulting in intrauterine growth restriction and perinatal lethality"

The measured growth outcome in the knockout.

Show evidence (1 reference)

PMID:31343991 SUPPORT Model Organism

"Deletion of Ccdc8 in mice impaired trophoblast migration and placental development"

Supports treating this model as informative for the placental node.

Constitutive Cul7 (p185) knockout mouse

The original Cul7 null, runted and perinatally lethal from respiratory distress, with defective trophoblast differentiation and abnormal placental vasculature.

Species

Mouse

Genotype

Cul7 (p185) null

Publication

PMID:12904573

Pathograph links

Abnormal Placental Development partially recapitulates fidelity: moderate Converges on the same placental trophoblast defect from a different 3-M gene.

Limitations: Perinatally lethal, so it does not model the viable human disease; the reported emphasis is vascular morphogenesis rather than the migration defect later shown for the 3-M ligase.

Readouts

Placental trophoblast differentiation

Direction: ALTERED

Interpretation: Histological correlate of the placental node.

Show evidence (1 reference)

PMID:12904573 SUPPORT Model Organism

"placentas show defects in the differentiation of the trophoblast lineage with an abnormal vascular structure"

The measured placental phenotype.

Show evidence (1 reference)

PMID:12904573 SUPPORT Model Organism

"embryos are runted and die immediately after birth because of respiratory distress"

Supports treating this model as informative for prenatal growth failure, while its perinatal lethality is the limitation recorded above.

OBSL1 frameshift sheep with brachygnathia, cardiomegaly and renal hypoplasia

A naturally occurring recessive syndrome with an OBSL1 frameshift that segregated in seven affected lambs and six obligate carriers. The authors propose an ovine model of 3-M syndrome type 2. Affected lambs are stillborn with short stature and skeletal abnormalities, plus cardiac and renal defects that extend beyond the usual human phenotype.

Species

Sheep

Genotype

Homozygous OBSL1 c.1716delC, predicted p.(Val573Trpfs*119)

Background

Australian Poll Merino/Merino flock

Publication

PMID:32933480

Pathograph links

Dysfunction of a 3-M Complex Component partially recapitulates fidelity: low A segregating predicted truncating OBSL1 variant provides a naturally occurring genetic counterpart to human OBSL1-related disease.

Limitations: Affected lambs are stillborn, so this is not a viable adult model or a model of postnatal growth. The study establishes segregation and predicts protein truncation; it does not measure OBSL1 protein loss, altered complex assembly, LL5-beta regulation or growth-factor responses. The severe cardiac and renal phenotype should not be transferred to human 3-M syndrome.

Readouts

OBSL1 genotype segregation

Direction: ALTERED

Interpretation: All seven affected lambs were homozygous for the deletion; obligate carriers were heterozygous.

Show evidence (1 reference)

PMID:32933480 SUPPORT PRIMARY RESULT Model Organism

"All seven affected animals were homozygous for the deletion, six obligate carrier animals were heterozygous and two phenotypically unaffected and one unrelated control animals were homozygous wildtype"

Segregation supports a likely causal OBSL1 frameshift in this flock; protein function and complex assembly were not directly assayed.

Show evidence (1 reference)

PMID:32933480 SUPPORT PRIMARY RESULT Model Organism

"All seven affected animals were homozygous for the deletion, six obligate carrier animals were heterozygous and two phenotypically unaffected and one unrelated control animals were homozygous wildtype"

Segregation supports a likely causal OBSL1 frameshift in this flock; protein function and complex assembly were not directly assayed.

Show evidence (1 reference)

PMID:32933480 SUPPORT BACKGROUND Model Organism

"Affected lambs are stillborn with various congenital defects as reflected in the name of the disease, as well as short stature, a short and broad cranium, a small thoracic cavity, thin ribs and brachysternum."

The study describes the established phenotype of the source flock, including its lethal course.

{ }

Source YAML

click to show

name: 3-M Syndrome
creation_date: "2026-08-27T01:40:00Z"
category: Mendelian
synonyms:
- 3M syndrome
- Miller-McKusick-Malvaux syndrome
- Le Merrer syndrome
- gloomy face syndrome
- Yakut short stature syndrome
- dolichospondylic dysplasia
description: >-
  3-M syndrome is an autosomal recessive growth disorder caused by biallelic pathogenic variants in CUL7, OBSL1
  or CCDC8. The encoded proteins participate in the 3-M complex and regulate membrane substrate targeting, microtubule
  behavior and cellular growth-factor responses. Severe prenatal-onset growth restriction persists after birth,
  with characteristic facial features and variable slender long bones and tall vertebral bodies. Intelligence is
  usually normal, although developmental delay and occasional intellectual disability have been reported. Musculoskeletal
  abnormalities, neonatal respiratory distress and male genital or pubertal abnormalities broaden the phenotype
  beyond isolated short stature. The three molecular subtypes overlap clinically; CUL7-related cases tend to be
  shorter than OBSL1-related cases, but the small number of CCDC8 cases limits genotype-phenotype comparisons. Cellular
  and mouse studies identify several candidate mechanisms whose relative contributions to human prenatal and postnatal
  growth remain unresolved.
disease_term:
  preferred_term: 3-M syndrome
  term:
    id: MONDO:0007477
    label: 3-M syndrome
parents:
- Autosomal recessive disease
- Primordial dwarfism
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  isds_skeletal_category:
  - classification_value: primordial_dwarfism_and_slender_bones
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al., PMID:36779427), group 21 "Primordial
      dwarfism and slender bone dysplasias". The three molecular forms correspond to NOS 21-0010 (CUL7, OMIM 273750),
      NOS 21-0020 (OBSL1, OMIM 612921), and NOS 21-0030 (CCDC8, OMIM 614205). Their substantial clinical overlap
      supports a grouped entry with separately mapped molecular subtypes.
has_subtypes:
- name: 3M1
  subtype_term:
    preferred_term: 3M syndrome 1
    term:
      id: MONDO:0010117
      label: 3M syndrome 1
  display_name: 3-M syndrome type 1 (CUL7-related)
  description: >-
    CUL7-related 3-M syndrome, the most frequently identified subtype in the initial molecular cohorts. Published
    series report more severe short stature on average than in OBSL1-related disease, with substantial clinical
    overlap. Corresponds to ISDS NOS 21-0010 and OMIM 273750.
  genes:
  - preferred_term: CUL7
    term:
      id: hgnc:21024
      label: CUL7
- name: 3M2
  subtype_term:
    preferred_term: 3M syndrome 2
    term:
      id: MONDO:0013039
      label: 3M syndrome 2
  display_name: 3-M syndrome type 2 (OBSL1-related)
  description: >-
    OBSL1-related 3-M syndrome, with clinical and radiographic overlap with CUL7-related disease and somewhat greater
    height on average in published comparisons. Corresponds to ISDS NOS 21-0020 and OMIM 612921.
  genes:
  - preferred_term: OBSL1
    term:
      id: hgnc:29092
      label: OBSL1
- name: 3M3
  subtype_term:
    preferred_term: 3M syndrome 3
    term:
      id: MONDO:0013627
      label: 3M syndrome 3
  display_name: 3-M syndrome type 3 (CCDC8-related)
  description: >-
    CCDC8-related 3-M syndrome. Few molecularly confirmed individuals have been reported, so comparative severity
    estimates remain uncertain. Corresponds to ISDS NOS 21-0030 and OMIM 614205.
  genes:
  - preferred_term: CCDC8
    term:
      id: hgnc:25367
      label: CCDC8
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    A worldwide population rate is not established. Published cohorts are clinically ascertained and founder populations
    should be considered separately.
- population: Yakut population, historical 2007 estimate
  subtype: 3M1
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 10
  rate_denominator: POPULATION
  notes: >-
    The authors estimated approximately 0.01%, based on at least 43 affected people. The normalized rate is approximate
    and should not be extrapolated worldwide.
  evidence:
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence rate of short stature syndrome with CUL7 mutation in Yakut is ∼0.01% (at least 43 patients among 440 000 people)"
    explanation: Population-specific historical estimate for a CUL7 founder-variant cohort.
    quote_role: PRIMARY_RESULT
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic (homozygous or compound heterozygous) pathogenic variants in CUL7, OBSL1 or CCDC8; heterozygous carriers
    are unaffected. Consanguinity and founder alleles are common in reported families.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "3-M syndrome is inherited in an autosomal recessive manner"
    explanation: >-
      GeneReviews states the inheritance pattern directly.
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If both parents are known to be heterozygous for a CCDC8, CUL7, or OBSL1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of inheriting neither of the familial pathogenic variants."
    explanation: >-
      Defines recurrence risks conditional on both parents being carriers; this does not establish complete penetrance.
    quote_role: REVIEW_SYNTHESIS
genetic:
- name: CUL7
  gene_term:
    preferred_term: CUL7
    term:
      id: hgnc:21024
      label: CUL7
  relationship_type: CAUSATIVE
  subtype: 3M1
  notes: >-
    CUL7 (6p21.1) encodes a large cullin-family scaffold that assembles an SCF-like E3 ubiquitin ligase with Skp1,
    FBXW8 (Fbx29/Fbw8) and ROC1/RBX1. Nonsense, frameshift and canonical splice variants predominate; missense variants
    cluster in the region required to recruit ROC1.
  case_fractions:
  - population: 3-M families with an identified mutation (Hanson et al. cohort)
    case_fraction_percent: 69.0
    notes: Most frequently mutated of the three 3-M genes.
    evidence:
    - reference: PMID:23018678
      reference_title: "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The prevalence of 3-M mutations was 69% CUL7, 23% OBSL1 and 8% CCDC8."
      explanation: >-
        Gene fraction among molecularly solved families in the Hanson et al. cohort; not a universal population
        proportion.
  evidence:
  - reference: PMID:16142236
    reference_title: "Identification of mutations in CUL7 in 3-M syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Functional studies indicated that the 3-M-associated CUL7 nonsense and missense mutations R1445X and H1464P, respectively, render CUL7 deficient in recruiting ROC1."
    explanation: >-
      The discovery study links patient-associated CUL7 variants to impaired ROC1 recruitment in functional assays.
- name: OBSL1
  gene_term:
    preferred_term: OBSL1
    term:
      id: hgnc:29092
      label: OBSL1
  relationship_type: CAUSATIVE
  subtype: 3M2
  notes: >-
    OBSL1 (2q35) encodes a cytoskeletal adaptor. The initial disease-gene report identified seven distinct null
    variants in ten families; this describes the discovery series rather than an exhaustive restriction on all pathogenic
    variant classes.
  case_fractions:
  - population: 3-M families with an identified mutation (Hanson et al. cohort)
    case_fraction_percent: 23.0
    evidence:
    - reference: PMID:23018678
      reference_title: "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The prevalence of 3-M mutations was 69% CUL7, 23% OBSL1 and 8% CCDC8."
      explanation: >-
        Gene fraction among molecularly solved families in the Hanson et al. cohort; not a universal population
        proportion.
  evidence:
  - reference: PMID:19481195
    reference_title: "The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we subsequently discovered seven distinct null mutations from 10 families within the gene OBSL1"
    explanation: >-
      The locus-mapping and mutation study that established OBSL1 as the second
      3-M gene.
- name: CCDC8
  gene_term:
    preferred_term: CCDC8
    term:
      id: hgnc:25367
      label: CCDC8
  relationship_type: CAUSATIVE
  subtype: 3M3
  notes: >-
    CCDC8 (19q13.32) is a single-exon gene. The initial exome study established biallelic inactivating variants
    as the cause of this rare molecular subtype.
  case_fractions:
  - population: 3-M families with an identified mutation (Hanson et al. cohort)
    case_fraction_percent: 8.0
    evidence:
    - reference: PMID:23018678
      reference_title: "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The prevalence of 3-M mutations was 69% CUL7, 23% OBSL1 and 8% CCDC8."
      explanation: >-
        Gene fraction among molecularly solved families in the Hanson et al. cohort; not a universal population
        proportion.
  evidence:
  - reference: PMID:21737058
    reference_title: "Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing now identifies mutations in CCDC8 as a cause of 3-M syndrome."
    explanation: >-
      The exome study that established CCDC8 as the third 3-M gene.
pathophysiology:
- name: Dysfunction of a 3-M Complex Component
  biological_scale: MOLECULAR
  description: >-
    Biallelic pathogenic variants impair CUL7, OBSL1 or CCDC8 function. CUL7 provides the scaffold of a ubiquitin
    ligase; OBSL1 and CCDC8 have adaptor and localization functions. Loss of either adaptor need not abolish the
    purified ligase catalytic activity. The experimental phenotypes below were studied in different cell types and
    genotypes and do not constitute one proven linear pathway.
  genes:
  - preferred_term: CUL7
    term:
      id: hgnc:21024
      label: CUL7
  - preferred_term: OBSL1
    term:
      id: hgnc:29092
      label: OBSL1
  - preferred_term: CCDC8
    term:
      id: hgnc:25367
      label: CCDC8
  role: trigger
  downstream:
  - target: Impaired Membrane Recruitment of the 3-M Complex
    description: Patient-derived variants impair membrane recruitment in cellular assays.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31343991
      reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "patient-derived mutations in 3-M genes disrupted membrane localization of the 3-M complex and accumulated LL5β."
      explanation: >-
        Tested patient-derived variants impair membrane localization and substrate regulation in cellular experiments.
      quote_role: PRIMARY_RESULT
  - target: Reduced Cellular Response to Growth Hormone
    description: OBSL1- and CCDC8-deficient patient fibroblasts have reduced responses to GH.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23018678
      reference_title: "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "activation of STAT5b and MAPK in response to GH was normal in CUL7(-/-) cells but reduced in OBSL1(-/-) and CCDC8(-/-) cells compared with controls."
      explanation: >-
        Patient fibroblasts show genotype-dependent GH responses; CUL7-deficient cells retained the measured response.
      quote_role: PRIMARY_RESULT
  - target: Reduced Cellular Response to IGF1
    description: CUL7- and OBSL1-deficient patient fibroblasts have reduced responses to IGF1.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23018678
      reference_title: "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Activation of AKT to IGF1 was reduced in CUL7(-/-) and OBSL1(-/-) cells at 5 min post-stimulation but normal in CCDC8(-/-) cells."
      explanation: Specifies the cellular endpoint, stimulation time and genotypes tested.
      quote_role: PRIMARY_RESULT
  - target: Reduced IGF2 Expression
    description: >-
      Patient fibroblasts have reduced IGF2 expression; the regulatory intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24148222
      reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."
      explanation: >-
        Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three
        control lines.
      quote_role: PRIMARY_RESULT
  - target: Increased H19 Expression
    description: >-
      Patient fibroblasts have increased H19 expression; the regulatory intermediates are unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24148222
      reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."
      explanation: >-
        Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three
        control lines.
      quote_role: PRIMARY_RESULT
  - target: Accelerated Microtubule Growth
    description: Depletion of 3-M proteins alters microtubule dynamics in studied cell lines.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24793695
      reference_title: "The 3M complex maintains microtubule and genome integrity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "First, loss of 3M proteins accelerates microtubule growth in both interphase and mitotic cells, implying a function for the 3M complex in either inhibiting microtubule growth or promoting microtubule catastrophe."
      explanation: Cell depletion experiments directly measured altered microtubule dynamics.
      quote_role: PRIMARY_RESULT
  - target: Reduced Growth Plate Proliferative-zone Cellularity
    description: Cartilage-specific Cul7 deletion produces a growth-plate cellularity defect in mice.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38367951
      reference_title: "Longitudinal skeletal growth and growth plate morphological characteristics of chondro-tissue specific CUL7 knockout mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "decreased number of cells in the proliferation zone"
      explanation: >-
        Histological cell number is reduced in cartilage-specific Cul7 knockout mice; this is not a direct proliferation-rate
        measurement.
      quote_role: PRIMARY_RESULT
  - target: Severe pre- and postnatal growth deficiency
    description: >-
      Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301654
      reference_title: "3-M Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "3-M syndrome is characterized by severe pre- and postnatal growth deficiency (final height five standard deviations below the mean)"
      explanation: >-
        Clinical syndrome-level observation; the cellular intermediates connecting the genetic defect to this manifestation
        are not established.
      directness: INDIRECT
  - target: Relative macrocephaly
    description: >-
      Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301654
      reference_title: "3-M Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"
      explanation: >-
        Clinical syndrome-level observation; the cellular intermediates connecting the genetic defect to this manifestation
        are not established.
      directness: INDIRECT
  - target: Triangular face
    description: >-
      Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301654
      reference_title: "3-M Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"
      explanation: >-
        Clinical syndrome-level observation; the cellular intermediates connecting the genetic defect to this manifestation
        are not established.
      directness: INDIRECT
  - target: Midface retrusion
    description: >-
      Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301654
      reference_title: "3-M Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"
      explanation: >-
        Clinical syndrome-level observation; the cellular intermediates connecting the genetic defect to this manifestation
        are not established.
      directness: INDIRECT
  - target: Fleshy nasal tip
    description: >-
      Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:20301654
      reference_title: "3-M Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"
      explanation: >-
        Clinical syndrome-level observation; the cellular intermediates connecting the genetic defect to this manifestation
        are not established.
      directness: INDIRECT
  - target: Slender long bones
    description: >-
      Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41437277
      reference_title: "3-M syndrome: evolution of the phenotype over time."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "| Slender long bones | 57/72 | 79% | 41/51 | 80% | 7/11 | 64% |"
      explanation: >-
        Clinical syndrome-level observation; the cellular intermediates connecting the genetic defect to this manifestation
        are not established.
      quote_role: REVIEW_SYNTHESIS
      directness: INDIRECT
  - target: Tall vertebral bodies
    description: >-
      Recognized clinical manifestation of the genetic disorder; the tissue-specific causal sequence remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:41437277
      reference_title: "3-M syndrome: evolution of the phenotype over time."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "3-M syndrome (OMIM# 273750, 612921, 614205) is a rare autosomal recessive disease characterized by severe pre- and post-natal growth retardation, bulbous nose, short thorax, prominent abdomen, slight slender tubular bones, tall vertebral bodies, and normal intelligence."
      explanation: >-
        Clinical syndrome-level observation; the cellular intermediates connecting the genetic defect to this manifestation
        are not established.
      directness: INDIRECT
  evidence:
  - reference: PMID:16142236
    reference_title: "Identification of mutations in CUL7 in 3-M syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CUL7 assembles an E3 ubiquitin ligase complex containing Skp1, Fbx29 (also called Fbw8) and ROC1 and promotes ubiquitination"
    explanation: >-
      CUL7 assembles a ubiquitin ligase; the tested CUL7 variants impair ROC1 recruitment. These findings do not
      establish universal loss of catalytic activity after OBSL1 or CCDC8 dysfunction.
    quote_role: PRIMARY_RESULT
  - reference: PMID:16142236
    reference_title: "Identification of mutations in CUL7 in 3-M syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the 3-M-associated CUL7 nonsense and missense mutations R1445X and H1464P, respectively, render CUL7 deficient in recruiting ROC1"
    explanation: >-
      CUL7 assembles a ubiquitin ligase; the tested CUL7 variants impair ROC1 recruitment. These findings do not
      establish universal loss of catalytic activity after OBSL1 or CCDC8 dysfunction.
    quote_role: PRIMARY_RESULT
  - reference: PMID:19481195
    reference_title: "The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "loss of OBSL1 leads to downregulation of CUL7, implying a role for OBSL1 in the maintenance of CUL7 protein levels"
    explanation: OBSL1 depletion can reduce CUL7 abundance in the studied cells.
    quote_role: PRIMARY_RESULT
  - reference: PMID:21737058
    reference_title: "Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "coimmunoprecipitation indicates a physical interaction between CCDC8 and OBSL1 but not CUL7"
    explanation: The discovery study supports an interaction through OBSL1.
    quote_role: PRIMARY_RESULT
- name: Impaired Membrane Recruitment of the 3-M Complex
  biological_scale: MOLECULAR
  description: >-
    CCDC8 phosphorylation normally promotes recruitment of OBSL1 and CUL7 to the plasma membrane. Tested patient-derived
    variants disrupt this localization, compromising membrane substrate targeting.
  cellular_components:
  - preferred_term: plasma membrane
    term:
      id: GO:0005886
      label: plasma membrane
  downstream:
  - target: Reduced Cellular Ubiquitination of LL5-beta
    description: >-
      Loss of membrane recruitment is the proposed cellular basis of reduced LL5-beta ubiquitination. OBSL1 and
      CCDC8 are dispensable for catalysis in the purified reaction.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31343991
      reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "CCDC8 promoted the polyubiquitylation of LL5β (Figure 5C), while knockdown of either CUL7 or CCDC8 reduced LL5β poly - ubiquitylation (Figure 5D)."
      explanation: >-
        Cellular overexpression and knockdown assays support altered substrate ubiquitination. The full experiment
        coexpressed FBXW8, CUL7, OBSL1 and CCDC8.
      quote_role: PRIMARY_RESULT
    - reference: PMID:31343991
      reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Dropout of either OBSL1 (lane 6) or CCDC8 (lane 7) did not impair LL5β polyubiquitylation in vitro."
      explanation: >-
        Separates localization-dependent substrate targeting from intrinsic catalytic activity.
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:31343991
    reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "patient-derived mutations in 3-M genes disrupted membrane localization of the 3-M complex and accumulated LL5β."
    explanation: >-
      Tested patient-derived variants impair membrane localization and substrate regulation in cellular experiments.
    quote_role: PRIMARY_RESULT
- name: Reduced Cellular Ubiquitination of LL5-beta
  biological_scale: MOLECULAR
  description: >-
    CUL7 or CCDC8 depletion reduces cellular LL5-beta polyubiquitination. This substrate-specific observation should
    not be generalized to loss of every ubiquitination reaction.
  biological_processes:
  - preferred_term: protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
    modifier: DECREASED
  downstream:
  - target: Accumulation of LL5-beta Protein
    description: Impaired ubiquitination and turnover contribute to increased LL5-beta abundance.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31343991
      reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "patient-derived mutations in 3-M genes disrupted membrane localization of the 3-M complex and accumulated LL5β."
      explanation: >-
        Tested patient-derived variants impair membrane localization and substrate regulation in cellular experiments.
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:31343991
    reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CCDC8 promoted the polyubiquitylation of LL5β (Figure 5C), while knockdown of either CUL7 or CCDC8 reduced LL5β poly - ubiquitylation (Figure 5D)."
    explanation: >-
      Cellular overexpression and knockdown assays support altered substrate ubiquitination. The full experiment
      coexpressed FBXW8, CUL7, OBSL1 and CCDC8.
    quote_role: PRIMARY_RESULT
- name: Accumulation of LL5-beta Protein
  biological_scale: MOLECULAR
  description: >-
    LL5-beta, encoded by PHLDB2, accumulates after disruption of the 3-M complex. The increase in differentiated
    Ccdc8-null mouse trophoblast cells was not accompanied by an increase in LL5-beta gene expression.
  genes:
  - preferred_term: PHLDB2
    term:
      id: hgnc:29573
      label: PHLDB2
  downstream:
  - target: Impaired Cell Migration
    description: >-
      LL5-beta overexpression phenocopies reduced migration in U2OS cells and supports a contribution of excess
      LL5-beta. The study did not establish it as the sole mediator by knockdown rescue.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31343991
      reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This observation is very similar to the finding that over- expression of LL5β in U2OS also inhibited cell migration and inva- sion"
      explanation: >-
        Overexpression phenocopies the migration defect; mediation remains incompletely resolved.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  evidence:
  - reference: PMID:31343991
    reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "patient-derived mutations in 3-M genes disrupted membrane localization of the 3-M complex and accumulated LL5β."
    explanation: >-
      Tested patient-derived variants impair membrane localization and substrate regulation in cellular experiments.
    quote_role: PRIMARY_RESULT
- name: Impaired Cell Migration
  biological_scale: CELLULAR
  description: >-
    CCDC8 depletion impairs migration and invasion in U2OS cells and mouse embryonic fibroblasts. In trophoblast
    cultures the migration defect is differentiation-dependent: Ccdc8-null SynT-II cells migrate less, whereas undifferentiated
    TSCs have migration similar to controls.
  biological_processes:
  - preferred_term: trophoblast cell migration
    term:
      id: GO:0061450
      label: trophoblast cell migration
    modifier: DECREASED
  downstream:
  - target: Abnormal Placental Development
    description: >-
      Impaired trophoblast migration is proposed to contribute to the placental phenotype. Cultured-cell and whole-animal
      findings support the model without isolating migration as the only cause.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31343991
      reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Deletion of Ccdc8 in mice impaired trophoblast migration and placental development, resulting in intrauterine growth restriction and perinatal lethality."
      explanation: Constitutive knockout establishes the placental and fetal growth phenotypes in mice.
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:31343991
    reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Ccdc8+/+ and Ccdc8 –/– TSCs showed similar migration speed in the transwell assay, but after induction to differentiate into SynT-II cells, Ccdc8–/– cells exhibited significantly reduced migration"
    explanation: >-
      Ccdc8-dependent migration was demonstrated after differentiation of mouse trophoblast stem cells into SynT-II
      cells, not in undifferentiated TSCs.
    quote_role: PRIMARY_RESULT
- name: Abnormal Placental Development
  biological_scale: TISSUE
  description: >-
    Constitutive Ccdc8 and Cul7 mouse knockouts have abnormal placental development. A single affected human CUL7
    fetus also showed abnormal chorionic villi and constricted intervillous spaces. Placental dysfunction may explain
    part of prenatal growth restriction; it does not by itself explain all fetal tissue abnormalities or postnatal
    short stature.
  biological_processes:
  - preferred_term: placenta development
    term:
      id: GO:0001890
      label: placenta development
    modifier: ABNORMAL
  downstream:
  - target: Intrauterine growth restriction
    description: >-
      Mouse evidence supports a placental contribution to prenatal growth failure; its magnitude in human disease
      remains uncertain.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:31343991
      reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Deletion of Ccdc8 in mice impaired trophoblast migration and placental development, resulting in intrauterine growth restriction and perinatal lethality."
      explanation: >-
        Evidence for a contribution to human growth is indirect because this causal experiment was in mice.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  evidence:
  - reference: PMID:31343991
    reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Deletion of Ccdc8 in mice impaired trophoblast migration and placental development, resulting in intrauterine growth restriction and perinatal lethality."
    explanation: Constitutive knockout establishes the placental and fetal growth phenotypes in mice.
    quote_role: PRIMARY_RESULT
  - reference: PMID:12904573
    reference_title: "Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "placentas show defects in the differentiation of the trophoblast lineage with an abnormal vascular structure"
    explanation: >-
      An independent 3-M gene knockout converges on the same placental
      trophoblast defect.
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a marked increase in the number of chorionic villi with numerous syncytial knots and intervillous lacuna constriction was observed"
    explanation: >-
      Placental histology from one affected 26-week CUL7 fetus, compared with an unaffected fetus; not established
      across all genotypes.
    quote_role: PRIMARY_RESULT
- name: Reduced Cellular Response to Growth Hormone
  biological_scale: CELLULAR
  description: >-
    Reduced GH-induced STAT5b and MAPK activation was found in OBSL1- and CCDC8-deficient patient fibroblasts; the
    assayed CUL7-deficient cells responded normally. These in vitro findings do not establish the cause of variable
    clinical GH treatment response.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: growth hormone receptor signaling pathway
    term:
      id: GO:0060396
      label: growth hormone receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:23018678
    reference_title: "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "activation of STAT5b and MAPK in response to GH was normal in CUL7(-/-) cells but reduced in OBSL1(-/-) and CCDC8(-/-) cells compared with controls."
    explanation: >-
      Patient fibroblasts show genotype-dependent GH responses; CUL7-deficient cells retained the measured response.
    quote_role: PRIMARY_RESULT
- name: Reduced Cellular Response to IGF1
  biological_scale: CELLULAR
  description: >-
    IGF1-induced AKT activation at five minutes was reduced in CUL7- and OBSL1-deficient patient fibroblasts, with
    normal responses in the assayed CCDC8-deficient cells.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: insulin-like growth factor receptor signaling pathway
    term:
      id: GO:0048009
      label: insulin-like growth factor receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:23018678
    reference_title: "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Activation of AKT to IGF1 was reduced in CUL7(-/-) and OBSL1(-/-) cells at 5 min post-stimulation but normal in CCDC8(-/-) cells."
    explanation: Specifies the cellular endpoint, stimulation time and genotypes tested.
    quote_role: PRIMARY_RESULT
- name: Reduced IGF2 Expression
  biological_scale: MOLECULAR
  description: >-
    Four patient fibroblast lines representing CUL7, OBSL1 and CCDC8 genotypes showed reduced IGF2 expression compared
    with three controls. Assayed H19 and IGF2 methylation regions did not differ, so this finding does not establish
    the imprinting defect seen in Silver-Russell syndrome.
  genes:
  - preferred_term: IGF2
    term:
      id: hgnc:5466
      label: IGF2
  downstream:
  - target: Reduced IGF-II Secretion
    description: >-
      Reduced transcript abundance accompanies reduced IGF-II secretion in the same patient fibroblast study.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24148222
      reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Levels of IGF-II secreted into conditioned cell culture medium were higher for control fibroblasts than those for 3-M fibroblasts (10.2±2.9 vs 0.6±0.9 ng/ml, P<0.01)."
      explanation: Conditioned-medium ELISA documents reduced secretion in cultured patient fibroblasts.
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:24148222
    reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."
    explanation: >-
      Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three control
      lines.
    quote_role: PRIMARY_RESULT
  - reference: PMID:24148222
    reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Methylation-specific PCR and pyrosequencing of the H19 ICR, H19 promotor and IGF2 DMR0 identified no differences in methylation between control and 3-M syndrome subjects, for both peripheral leucocyte and fibroblast-derived DNA."
    explanation: >-
      The assayed methylation regions were unchanged; other regulatory mechanisms remain unresolved.
    quote_role: PRIMARY_RESULT
- name: Increased H19 Expression
  biological_scale: MOLECULAR
  description: >-
    H19 expression was increased in the same four patient fibroblast lines. This is a parallel expression finding;
    a causal H19-to-IGF2 regulatory step was not demonstrated.
  genes:
  - preferred_term: H19
    term:
      id: hgnc:4713
      label: H19
  evidence:
  - reference: PMID:24148222
    reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."
    explanation: >-
      Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three control
      lines.
    quote_role: PRIMARY_RESULT
- name: Reduced IGF-II Secretion
  biological_scale: CELLULAR
  description: >-
    IGF-II in conditioned medium was lower in patient than control fibroblasts. Reduced autocrine or paracrine growth
    stimulation is a proposed contribution to growth failure, not a demonstrated growth-plate defect in patients.
  downstream:
  - target: Severe pre- and postnatal growth deficiency
    description: >-
      The authors propose reduced local IGF-II as one explanation for growth failure; fibroblast data do not establish
      the mechanism in human growth plates.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24148222
      reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Loss of autocrine IGF-II in the growth plate may be associated with the short stature seen in children with 3-M syndrome."
      explanation: >-
        Author-proposed link from fibroblast secretion to clinical growth, without growth-plate or rescue evidence.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  evidence:
  - reference: PMID:24148222
    reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Levels of IGF-II secreted into conditioned cell culture medium were higher for control fibroblasts than those for 3-M fibroblasts (10.2±2.9 vs 0.6±0.9 ng/ml, P<0.01)."
    explanation: Conditioned-medium ELISA documents reduced secretion in cultured patient fibroblasts.
    quote_role: PRIMARY_RESULT
- name: Accelerated Microtubule Growth
  biological_scale: CELLULAR
  description: >-
    Loss of 3-M proteins accelerates microtubule growth in experimental cell lines. Effects depend on cell context
    and expression; this branch is not asserted to be downstream of membrane localization or LL5-beta accumulation.
  biological_processes:
  - preferred_term: microtubule cytoskeleton organization
    term:
      id: GO:0000226
      label: microtubule cytoskeleton organization
    modifier: ABNORMAL
  downstream:
  - target: Delayed Mitotic Progression
    description: >-
      The study links altered microtubule dynamics to chromosome congression defects and mitotic delay.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24793695
      reference_title: "The 3M complex maintains microtubule and genome integrity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Together, these results indicated that CUL7 depletion delayed mitotic progression due to impaired chromosome congression at prometaphase and also causes defects in cytokinesis."
      explanation: >-
        Live-cell experiments demonstrate both mitotic delay and cytokinesis defects after CUL7 depletion.
      quote_role: PRIMARY_RESULT
  - target: Defective Cytokinesis
    description: >-
      Microtubule abnormalities and cytokinesis failure occur after CUL7 depletion; the complete causal sequence
      remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:24793695
      reference_title: "The 3M complex maintains microtubule and genome integrity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Together, these results indicated that CUL7 depletion delayed mitotic progression due to impaired chromosome congression at prometaphase and also causes defects in cytokinesis."
      explanation: >-
        Live-cell experiments demonstrate both mitotic delay and cytokinesis defects after CUL7 depletion.
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:24793695
    reference_title: "The 3M complex maintains microtubule and genome integrity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "First, loss of 3M proteins accelerates microtubule growth in both interphase and mitotic cells, implying a function for the 3M complex in either inhibiting microtubule growth or promoting microtubule catastrophe."
    explanation: Cell depletion experiments directly measured altered microtubule dynamics.
    quote_role: PRIMARY_RESULT
- name: Delayed Mitotic Progression
  biological_scale: CELLULAR
  description: >-
    CUL7 depletion delays chromosome congression and mitotic progression in cultured cells. Spindle-checkpoint manipulation
    can remove the delay without demonstrating restoration of chromosome segregation fidelity.
  biological_processes:
  - preferred_term: mitotic cell cycle
    term:
      id: GO:0000278
      label: mitotic cell cycle
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24793695
    reference_title: "The 3M complex maintains microtubule and genome integrity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Together, these results indicated that CUL7 depletion delayed mitotic progression due to impaired chromosome congression at prometaphase and also causes defects in cytokinesis."
    explanation: >-
      Live-cell experiments demonstrate both mitotic delay and cytokinesis defects after CUL7 depletion.
    quote_role: PRIMARY_RESULT
- name: Defective Cytokinesis
  biological_scale: CELLULAR
  description: >-
    CUL7 depletion causes cytokinesis defects and increased ploidy. Two CUL7-mutant patient fibroblast lines also
    showed increased ploidy. Wild-type CUL7 rescue was demonstrated in CUL7-depleted experimental cells, not in
    patient fibroblasts.
  biological_processes:
  - preferred_term: cytokinesis
    term:
      id: GO:0000910
      label: cytokinesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24793695
    reference_title: "The 3M complex maintains microtubule and genome integrity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Together, these results indicated that CUL7 depletion delayed mitotic progression due to impaired chromosome congression at prometaphase and also causes defects in cytokinesis."
    explanation: >-
      Live-cell experiments demonstrate both mitotic delay and cytokinesis defects after CUL7 depletion.
    quote_role: PRIMARY_RESULT
  - reference: PMID:24793695
    reference_title: "The 3M complex maintains microtubule and genome integrity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Ectopic expression of wild-type CUL7 effectively rescued the defects in CUL7 depleted cells, reducing the tetraploid/polyploid cells to 5.2%."
    explanation: >-
      Rescue experiment in CUL7-depleted cells supports the specificity of the observed cellular defect.
    quote_role: PRIMARY_RESULT
- name: Reduced Growth Plate Proliferative-zone Cellularity
  biological_scale: TISSUE
  description: >-
    Cartilage-specific Cul7 knockout mice have fewer cells in the growth-plate proliferative zone, disorganized
    chondrocyte columns, altered matrix and short deformed limbs. The comparator was Cul7fl/+;Col2a1-CreERT2. This
    supports a tissue-specific skeletal role for CUL7, without proving a proliferation-rate defect, an upstream
    GH/IGF cause, or equivalent effects of OBSL1 and CCDC8.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  downstream:
  - target: Severe pre- and postnatal growth deficiency
    description: >-
      The mouse cartilage phenotype supports a possible contribution to skeletal growth failure; human prenatal
      growth and non-skeletal features require additional explanations.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38367951
      reference_title: "Longitudinal skeletal growth and growth plate morphological characteristics of chondro-tissue specific CUL7 knockout mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "mice had abnormally short and deformed limbs"
      explanation: Indirect support for human short stature from cartilage-specific Cul7 knockout mice.
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
  evidence:
  - reference: PMID:38367951
    reference_title: "Longitudinal skeletal growth and growth plate morphological characteristics of chondro-tissue specific CUL7 knockout mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "decreased number of cells in the proliferation zone"
    explanation: >-
      Histological cell number is reduced in cartilage-specific Cul7 knockout mice; this is not a direct proliferation-rate
      measurement.
    quote_role: PRIMARY_RESULT
phenotypes:
- category: Growth
  name: Severe pre- and postnatal growth deficiency
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "3-M syndrome is characterized by severe pre- and postnatal growth deficiency (final height five standard deviations below the mean)"
    explanation: >-
      The defining feature, quantified by GeneReviews.
- category: Growth
  name: Intrauterine growth restriction
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:19481195
    reference_title: "The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "3-M syndrome is an autosomal-recessive primordial growth disorder characterized by significant intrauterine and postnatal growth restriction"
    explanation: >-
      Prenatal onset is what makes 3-M a primordial rather than a postnatal growth disorder.
- category: Craniofacial
  name: Relative macrocephaly
  phenotype_term:
    preferred_term: Relative macrocephaly
    term:
      id: HP:0004482
      label: Relative macrocephaly
  description: >-
    Head size is relatively preserved compared with markedly reduced body size; absolute head circumference can
    vary.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"
    explanation: >-
      GeneReviews lists relative macrocephaly among the characteristic facial
      features.
- category: Craniofacial
  name: Triangular face
  phenotype_term:
    preferred_term: Triangular face
    term:
      id: HP:0000325
      label: Triangular face
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"
    explanation: >-
      Listed by GeneReviews among the characteristic facial features.
- category: Craniofacial
  name: Dolichocephaly
  phenotype_term:
    preferred_term: Dolichocephaly
    term:
      id: HP:0000268
      label: Dolichocephaly
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"
    explanation: >-
      Listed by GeneReviews among the characteristic facial features.
- category: Craniofacial
  name: Midface retrusion
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"
    explanation: >-
      Listed by GeneReviews among the characteristic facial features.
- category: Craniofacial
  name: Fleshy nasal tip
  phenotype_term:
    preferred_term: Fleshy (bulbous) nasal tip
    term:
      id: HP:0000414
      label: Bulbous nose
  description: >-
    A bulbous nasal tip is a characteristic facial feature that can remain recognizable as other features change
    with age.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characteristic facies (relative macrocephaly, dolichocephaly, triangular face, midface retrusion, thick eyebrows, fleshy nasal tip, long philtrum"
    explanation: >-
      Listed by GeneReviews among the characteristic facial features.
- category: Craniofacial
  name: Thick eyebrows
  phenotype_term:
    preferred_term: Thick eyebrow
    term:
      id: HP:0000574
      label: Thick eyebrow
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thick eyebrows, fleshy nasal tip, long philtrum"
    explanation: >-
      Listed by GeneReviews among the characteristic facial features.
- category: Craniofacial
  name: Long philtrum
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thick eyebrows, fleshy nasal tip, long philtrum"
    explanation: >-
      Listed by GeneReviews among the characteristic facial features.
- category: Craniofacial
  name: Pointed chin
  phenotype_term:
    preferred_term: Pointed chin
    term:
      id: HP:0000307
      label: Pointed chin
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thick vermilion of the upper and low lips, and pointed chin"
    explanation: >-
      Listed by GeneReviews among the characteristic facial features.
- category: Skeletal
  name: Slender long bones
  phenotype_term:
    preferred_term: Slender long bones
    term:
      id: HP:0003100
      label: Slender long bone
  diagnostic: true
  description: >-
    Slender long bones are characteristic but variable. Table 1 of the 2025 review reported 57/72 CUL7, 41/51 OBSL1
    and 7/11 CCDC8 cases; the separately described Yakut founder cohort rarely had this radiographic finding.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Slender long bones | 57/72 | 79% | 41/51 | 80% | 7/11 | 64% |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, the characteristic radiological findings for 3‐M syndrome(slender tubular bones or tall vertebral bodies) were observed in few patients"
    explanation: >-
      The Yakut CUL7 founder cohort illustrates population-associated radiographic variability.
    quote_role: PRIMARY_RESULT
- category: Skeletal
  name: Tall vertebral bodies
  phenotype_term:
    preferred_term: Tall vertebral bodies with reduced anteroposterior diameter
    term:
      id: HP:0004570
      label: Increased vertebral height
  description: >-
    The spinal counterpart of the slender long bones, and the second half of the classic radiographic pair. Note
    the older literature describes the vertebral bodies as "foreshortened" - referring to the reduced anteroposterior
    diameter, not to reduced height, which is increased.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "3-M syndrome (OMIM# 273750, 612921, 614205) is a rare autosomal recessive disease characterized by severe pre- and post-natal growth retardation, bulbous nose, short thorax, prominent abdomen, slight slender tubular bones, tall vertebral bodies, and normal intelligence."
    explanation: >-
      Names tall vertebral bodies among the defining features of the disorder.
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Tall vertebral bodies | 45/71 | 63% | 33/50 | 66% | 5/11 | 45% |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
- category: Skeletal
  name: Short neck
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features of 3-M syndrome include short, broad neck, prominent trapezii"
    explanation: >-
      Listed by GeneReviews among the additional skeletal features.
- category: Skeletal
  name: Short thorax
  phenotype_term:
    preferred_term: Short thorax
    term:
      id: HP:0010306
      label: Short thorax
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae"
    explanation: >-
      Listed by GeneReviews among the additional skeletal features.
- category: Skeletal
  name: Pectus carinatum
  phenotype_term:
    preferred_term: Pectus carinatum
    term:
      id: HP:0000768
      label: Pectus carinatum
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae"
    explanation: >-
      GeneReviews records pectus carinatum or excavatum; carinatum is bound here and excavatum is curated as its
      own phenotype.
- category: Skeletal
  name: Pectus excavatum
  phenotype_term:
    preferred_term: Pectus excavatum
    term:
      id: HP:0000767
      label: Pectus excavatum
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae"
    explanation: >-
      The alternative chest-wall deformity recorded by GeneReviews.
- category: Skeletal
  name: Winged scapulae
  phenotype_term:
    preferred_term: Winged scapulae
    term:
      id: HP:0003691
      label: Scapular winging
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae"
    explanation: >-
      Listed by GeneReviews among the additional skeletal features.
- category: Skeletal
  name: Thoracic kyphoscoliosis
  phenotype_term:
    preferred_term: Thoracic kyphoscoliosis
    term:
      id: HP:0002751
      label: Kyphoscoliosis
  description: >-
    A recognized spinal manifestation; annual assessment is recommended. A surveillance recommendation alone does
    not establish a progressive course.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta"
    explanation: >-
      Listed by GeneReviews among the additional skeletal features.
- category: Skeletal
  name: Hyperlordosis
  phenotype_term:
    preferred_term: Hyperlordosis
    term:
      id: HP:0003307
      label: Hyperlordosis
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta"
    explanation: >-
      Listed by GeneReviews among the additional skeletal features.
- category: Skeletal
  name: Spina bifida occulta
  phenotype_term:
    preferred_term: Spina bifida occulta
    term:
      id: HP:0003298
      label: Spina bifida occulta
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta"
    explanation: >-
      Listed by GeneReviews among the additional skeletal features.
- category: Skeletal
  name: Clinodactyly of the fifth fingers
  phenotype_term:
    preferred_term: Clinodactyly of the 5th finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips"
    explanation: >-
      Listed by GeneReviews among the additional skeletal features.
- category: Skeletal
  name: Joint hypermobility
  phenotype_term:
    preferred_term: Generalized or distal joint hypermobility
    term:
      id: HP:0001382
      label: Joint hypermobility
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips"
    explanation: >-
      Listed by GeneReviews among the additional skeletal features.
- category: Skeletal
  name: Dislocated hips
  phenotype_term:
    preferred_term: Hip dislocation
    term:
      id: HP:0002827
      label: Hip dislocation
  description: >-
    GeneReviews recommends assessment at every infant visit, particularly where walking is delayed.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips"
    explanation: >-
      Listed by GeneReviews among the additional skeletal features.
- category: Skeletal
  name: Prominent heels
  phenotype_term:
    preferred_term: Prominent heels
    term:
      id: HP:0012428
      label: Prominent calcaneus
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dislocated hips, prominent heels, and pes planus"
    explanation: >-
      Listed by GeneReviews among the additional skeletal features.
- category: Skeletal
  name: Pes planus
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dislocated hips, prominent heels, and pes planus"
    explanation: >-
      Listed by GeneReviews among the additional skeletal features.
- category: Endocrine
  name: Hypogonadism in males
  phenotype_term:
    preferred_term: Hypogonadism (males)
    term:
      id: HP:0000135
      label: Hypogonadism
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Males with 3-M syndrome can have hypogonadism and occasionally hypospadias."
    explanation: >-
      GeneReviews records hypogonadism as a male-restricted feature.
  - reference: PMID:40974508
    reference_title: "Long-term follow-up of growth and puberty in 3-M syndrome: effects of growth hormone therapy and response variability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pubertal arrest was noted in seven male patients, while two female siblings and one male patient experienced rapidly progressive puberty."
    explanation: >-
      Recent retrospective cohort documents variable pubertal trajectories; the abstract does not provide a denominator
      restricted to pubertally assessable males.
    quote_role: PRIMARY_RESULT
  - reference: PMID:38847008
    reference_title: "Gonadal Failure in a Male With 3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Subsequently, a regression of testicular volumes, increased gonadotropin levels, and reduced (although normal) testosterone levels were observed."
    explanation: >-
      A CUL7-related case developed gonadal dysfunction after spontaneous pubertal progression; hormone and testicular
      findings support longitudinal endocrine monitoring.
  description: >-
    Male gonadal dysfunction may emerge as arrested puberty after spontaneous onset. It is variable: hypogonadism
    was not observed in the historical Yakut cohort.
- category: Genitourinary
  name: Hypospadias
  phenotype_term:
    preferred_term: Hypospadias
    term:
      id: HP:0000047
      label: Hypospadias
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Males with 3-M syndrome can have hypogonadism and occasionally hypospadias."
    explanation: >-
      GeneReviews records hypospadias as an occasional male finding.
- category: Head and Neck
  name: Frontal bossing
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  description: >-
    Reported in the genotype-stratified literature review; the quoted row preserves its feature-specific denominators.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Frontal bossing | 76/90 | 84% | 46/59 | 78% | 11/12 | 92% |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
- category: Head and Neck
  name: Anteverted nares
  phenotype_term:
    preferred_term: Anteverted nares
    term:
      id: HP:0000463
      label: Anteverted nares
  description: >-
    Reported in the genotype-stratified literature review; the quoted row preserves its feature-specific denominators.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Anteverted nares | 58/63 | 92% | 35/44 | 80% | 8/12 | 67% |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
- category: Head and Neck
  name: Protruding ears
  phenotype_term:
    preferred_term: Protruding ear
    term:
      id: HP:0000411
      label: Protruding ear
  description: >-
    Reported in the genotype-stratified literature review; the quoted row preserves its feature-specific denominators.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Prominent ears | 35/53 | 66% | 23/37 | 62% | 5/9 | 56% |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
- category: Musculoskeletal
  name: Squared-off shoulders
  phenotype_term:
    preferred_term: Squared off shoulders
    term:
      id: HP:6000464
      label: Squared off shoulders
  description: >-
    Reported in the genotype-stratified literature review; the quoted row preserves its feature-specific denominators.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Squared-off shoulders | 28/35 | 80% | 16/23 | 70% | 3/7 | 43% |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
- category: Abdominal
  name: Protuberant abdomen
  phenotype_term:
    preferred_term: Protuberant abdomen
    term:
      id: HP:0001538
      label: Protuberant abdomen
  description: >-
    Reported in the genotype-stratified literature review; the quoted row preserves its feature-specific denominators.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Protuberant abdomen | 30/35 | 86% | 22/27 | 81% | 0/1 | NA |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
- category: Musculoskeletal
  name: Flared metaphyses
  phenotype_term:
    preferred_term: Flared metaphysis
    term:
      id: HP:0003015
      label: Flared metaphysis
  description: >-
    Reported in the genotype-stratified literature review; the quoted row preserves its feature-specific denominators.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Flared metaphyses | 30/33 | 91% | 17/23 | 74% | 1/1 | NA |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
- category: Musculoskeletal
  name: Diaphyseal constriction
  phenotype_term:
    preferred_term: Slender long bones with narrow diaphyses
    term:
      id: HP:0004993
      label: Slender long bones with narrow diaphyses
  description: >-
    Narrow diaphyses accompany the characteristic slender long bones; the table records constriction separately
    from overall slenderness.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Diaphyseal constriction | 37/43 | 86% | 24/28 | 86% | 1/1 | NA |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
- category: Neurological
  name: Psychomotor developmental delay
  phenotype_term:
    preferred_term: Psychomotor developmental delay
    term:
      id: HP:0012758
      label: Neurodevelopmental delay
  description: >-
    Psychomotor delay was reported in 8/45 CUL7, 5/25 OBSL1 and 1/5 CCDC8 cases with available data. The pooled
    reports do not specify a uniform age or developmental-domain assessment, so a broad neurodevelopmental-delay
    term is used. This does not imply intellectual disability; intelligence is usually normal.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Psychomotor delay | 8/45 | 18% | 5/25 | 20% | 1/5 | 20% |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
- category: Limbs
  name: Single transverse palmar crease
  phenotype_term:
    preferred_term: Single transverse palmar crease
    term:
      id: HP:0000954
      label: Single transverse palmar crease
  description: >-
    Reported in the genotype-stratified literature review; the quoted row preserves its feature-specific denominators.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Unique transverse palmar crease | 14/22 | 64% | 2/9 | 22% | 0/0 | NA |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
- category: Musculoskeletal
  name: Scoliosis
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  description: >-
    Reported in the genotype-stratified literature review; the quoted row preserves its feature-specific denominators.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Scoliosis | 11/62 | 18% | 13/48 | 27% | 2/12 | 17% |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
- category: Skin
  name: Midline facial vascular mark
  phenotype_term:
    preferred_term: Midline facial haemangioma
  description: >-
    Reported in the genotype-stratified literature review; the quoted row preserves its feature-specific denominators.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Midline facial haemangioma | 11/37 | 30% | 6/32 | 19% | 2/5 | 40% |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    Needs term/NTR: no precise HPO binding was identified for this source-specific vascular mark. It is not assumed
    to be an infantile vascular tumor or a port-wine stain. OLS4 hp search q="midline facial haemangioma" (2026-09-21)
    returned no results.
- category: Eye
  name: Lower eyelid fat pads
  phenotype_term:
    preferred_term: Lower eyelid fat pads
  description: >-
    Reported in the genotype-stratified literature review; the quoted row preserves its feature-specific denominators.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Lower eyelid fat pads | 18/54 | 33% | 13/41 | 32% | 0/6 | 0% |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    Needs term/NTR: no precise HPO binding was identified for lower eyelid fat pads. This finding is not equated
    with eyelid edema. OLS4 hp search q="lower eyelid fat pads" (2026-09-21) returned Blepharochalasis (HP:0010749),
    which does not denote lower eyelid fat pads.
- category: Head and Neck
  name: Prominent central tubercle of the upper lip
  phenotype_term:
    preferred_term: Prominent central tubercle of upper lip
  description: >-
    Reported in the genotype-stratified literature review; the quoted row preserves its feature-specific denominators.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Prominent central tubercle of upper lip | 21/37 | 57% | 17/23 | 74% | 2/5 | 40% |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    Needs term/NTR: no precise HPO binding was identified for this finding. OLS4 hp search q="prominent central
    tubercle upper lip" (2026-09-21) returned no results.
- category: Musculoskeletal
  name: Transverse chest groove
  phenotype_term:
    preferred_term: Transverse chest groove
  description: >-
    Reported in the genotype-stratified literature review; the quoted row preserves its feature-specific denominators.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "| Chest groove | 14/27 | 52% | 12/25 | 48% | 2/7 | 29% |"
    explanation: >-
      Table 1 reports feature-specific denominators for CUL7, OBSL1 and CCDC8, respectively. These are literature-ascertained
      cases, sometimes scored from photographs; the 43 Yakut founder-variant cases were excluded. Counts are not
      population frequencies.
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    Needs term/NTR: no precise HPO binding was identified for this finding. OLS4 hp search q="transverse chest groove"
    (2026-09-21) returned no results.
- category: Head and Neck
  name: Thick upper lip vermilion
  phenotype_term:
    preferred_term: Thick upper lip vermilion
    term:
      id: HP:0000215
      label: Thick upper lip vermilion
  description: Thick vermilion is part of the characteristic facial phenotype.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thick vermilion of the upper and low lips"
    explanation: GeneReviews explicitly describes involvement of both lips.
    quote_role: REVIEW_SYNTHESIS
- category: Head and Neck
  name: Thick lower lip vermilion
  phenotype_term:
    preferred_term: Thick lower lip vermilion
    term:
      id: HP:0000179
      label: Thick lower lip vermilion
  description: Thick vermilion is part of the characteristic facial phenotype.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "thick vermilion of the upper and low lips"
    explanation: GeneReviews explicitly describes involvement of both lips.
    quote_role: REVIEW_SYNTHESIS
- category: Musculoskeletal
  name: Broad neck
  phenotype_term:
    preferred_term: Broad neck
    term:
      id: HP:0000475
      label: Broad neck
  description: Recognized additional musculoskeletal feature.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features of 3-M syndrome include short, broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips, prominent heels, and pes planus."
    explanation: GeneReviews lists this feature.
    quote_role: REVIEW_SYNTHESIS
- category: Musculoskeletal
  name: Prominent trapezius muscles
  phenotype_term:
    preferred_term: Prominent trapezii
  description: Recognized additional musculoskeletal feature.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional features of 3-M syndrome include short, broad neck, prominent trapezii, pectus carinatum/excavatum, short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis, hyperlordosis, spina bifida occulta, clinodactyly of the fifth fingers, generalized or distal joint hypermobility, dislocated hips, prominent heels, and pes planus."
    explanation: GeneReviews lists this feature.
    quote_role: REVIEW_SYNTHESIS
  notes: >-
    Needs term/NTR: retained as a specific unbound finding rather than equated with muscle hypertrophy. OLS4 hp
    search q="prominent trapezius" (2026-09-21) returned no results.
- category: Neurological
  name: Hypotonia
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  description: >-
    Reported in 37/43 patients in the Yakut CUL7 founder cohort; this count should not be generalized to all molecular
    subtypes.
  evidence:
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscular hypotonia | 25 (100) | 7 (88) | 5 (100) | 0 | 37 (86)"
    explanation: >-
      Table 2 gives age-group counts followed by the total count and percentage in the 43-person founder cohort.
    quote_role: PRIMARY_RESULT
- category: Head and Neck
  name: Hypertelorism
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  description: >-
    Reported in 19/43 patients in the Yakut CUL7 founder cohort; this count should not be generalized to all molecular
    subtypes.
  evidence:
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertelorism | 9 (36) | 4 (50) | 1 (20) | 5 (100) | 19 (44)"
    explanation: >-
      Table 2 gives age-group counts followed by the total count and percentage in the 43-person founder cohort.
    quote_role: PRIMARY_RESULT
- category: Eye
  name: Epicanthus
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  description: >-
    Reported in 17/43 patients in the Yakut CUL7 founder cohort; this count should not be generalized to all molecular
    subtypes.
  evidence:
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epicanthus | 14 (56) | 1 (12) | 2 (40) | 0 | 17 (40)"
    explanation: >-
      Table 2 gives age-group counts followed by the total count and percentage in the 43-person founder cohort.
    quote_role: PRIMARY_RESULT
- category: Hepatobiliary
  name: Hepatomegaly
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  description: >-
    Reported in 5/43 patients in the Yakut CUL7 founder cohort; this count should not be generalized to all molecular
    subtypes.
  evidence:
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hepatomegaly | 5 (20) | 0 | 0 | 0 | 5 (12)"
    explanation: >-
      Table 2 gives age-group counts followed by the total count and percentage in the 43-person founder cohort.
    quote_role: PRIMARY_RESULT
- category: Head and Neck
  name: Dysplastic ears
  phenotype_term:
    preferred_term: Abnormal pinna morphology
    term:
      id: HP:0000377
      label: Abnormal pinna morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  description: >-
    Reported in 20/43 patients in the Yakut CUL7 founder cohort; this count should not be generalized to all molecular
    subtypes.
  evidence:
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysplasia of ears | 11 (40) | 4 (50) | 5 (100) | 0 | 20 (47)"
    explanation: >-
      Table 2 gives age-group counts followed by the total count and percentage in the 43-person founder cohort.
    quote_role: PRIMARY_RESULT
- category: Limbs
  name: Brachydactyly
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  description: >-
    Common in the reported Yakut CUL7 founder cohort; the source describes small hands and feet as micromelia of
    the hands and feet.
  evidence:
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A short neck, short and wide thorax, brachydactyly, micromelia of the hands and feet and prominent heels were observed in >95% of the patients in all generations"
    explanation: Describes the high prevalence of these features within this specific founder cohort.
    quote_role: PRIMARY_RESULT
- category: Limbs
  name: Small hands
  phenotype_term:
    preferred_term: Small hand
    term:
      id: HP:0200055
      label: Small hand
  description: >-
    Common in the reported Yakut CUL7 founder cohort; the source describes small hands and feet as micromelia of
    the hands and feet.
  evidence:
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A short neck, short and wide thorax, brachydactyly, micromelia of the hands and feet and prominent heels were observed in >95% of the patients in all generations"
    explanation: Describes the high prevalence of these features within this specific founder cohort.
    quote_role: PRIMARY_RESULT
- category: Limbs
  name: Short feet
  phenotype_term:
    preferred_term: Short foot
    term:
      id: HP:0001773
      label: Short foot
  description: >-
    Common in the reported Yakut CUL7 founder cohort; the source describes small hands and feet as micromelia of
    the hands and feet.
  evidence:
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A short neck, short and wide thorax, brachydactyly, micromelia of the hands and feet and prominent heels were observed in >95% of the patients in all generations"
    explanation: Describes the high prevalence of these features within this specific founder cohort.
    quote_role: PRIMARY_RESULT
- category: Head and Neck
  name: Depressed nasal bridge
  phenotype_term:
    preferred_term: Depressed nasal bridge
    term:
      id: HP:0005280
      label: Depressed nasal bridge
  description: Documented in longitudinally followed CUL7-related disease.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On physical examination, he had slightly depressed nasal bridge, bulbous nasal tip pointing upwards, slightly pointed chin, bilateral brachydactyly, and single transverse palmar crease on the right hand."
    explanation: Findings in patient 1 at age 12 years.
    quote_role: PRIMARY_RESULT
- category: Abdominal
  name: Diastasis recti
  phenotype_term:
    preferred_term: Diastasis recti
    term:
      id: HP:0001540
      label: Diastasis recti
  description: Observed with a protuberant abdomen in an individual with CUL7-related disease.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The examination showed a slightly protuberant abdomen with diastasis recti."
    explanation: Individual longitudinal case observation; no general frequency inferred.
    quote_role: PRIMARY_RESULT
- category: Respiratory
  name: Neonatal respiratory distress
  phenotype_term:
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  description: >-
    In the Yakut CUL7 founder cohort, 18/43 infants had severe asphyxia and respiratory distress at birth and 11/43
    required ventilation. Risk outside that cohort is not quantified by these data.
  evidence:
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total, 18 (41.9%) infants had severe asphyxia and respiratory distress at birth and 11 (25.6%) infants required mechanical ventilation."
    explanation: Clinical observation in the 43-person Yakut founder cohort.
    quote_role: PRIMARY_RESULT
- category: Musculoskeletal
  name: Delayed bone age
  phenotype_term:
    preferred_term: Delayed skeletal maturation
    term:
      id: HP:0002750
      label: Delayed skeletal maturation
  description: >-
    Delayed bone age was reported in all 24 patients in a recent CUL7/OBSL1 cohort, and can normalize with age in
    other series.
  evidence:
  - reference: PMID:40974508
    reference_title: "Long-term follow-up of growth and puberty in 3-M syndrome: effects of growth hormone therapy and response variability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysmorphic features characteristic of 3-M syndrome and delayed bone age were observed in all patients."
    explanation: Retrospective cohort of 24 genetically confirmed patients.
    quote_role: PRIMARY_RESULT
- category: Endocrine
  name: Growth hormone deficiency
  phenotype_term:
    preferred_term: Decreased response to growth hormone stimulation test
    term:
      id: HP:0000824
      label: Decreased response to growth hormone stimulation test
  description: >-
    Most tested patients have normal peak GH, but documented GH deficiency can coexist. A genetically confirmed
    CUL7 case had severe deficiency and limited long-term response to replacement.
  evidence:
  - reference: PMID:23517720
    reference_title: "3-M syndrome associated with growth hormone deficiency: 18 year follow-up of a patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient also exhibited severe GHD (GH <5 ng/ml) and from the age of 18 months was treated with rhGH."
    explanation: Single molecularly confirmed patient; refutes an absolute exclusion of GH deficiency.
    quote_role: PRIMARY_RESULT
- category: Neurological
  name: Intellectual disability
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  description: >-
    Occasional intellectual disability has been reported in OBSL1-related cases, despite usually normal intelligence
    across 3-M syndrome. The literature review is small and does not establish a genotype-specific causal mechanism.
  evidence:
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It should be noted that only patients with variants in OBSL1 presented with intellectual disability, while the majority of patients with CUL7- or CCDC8-related 3-M syndrome and available neuropsychological assessment data had normal intellect."
    explanation: >-
      Genotype distribution in the reviewed reports; normal intellect was recorded in 20/22 OBSL1 cases with relevant
      data.
    quote_role: REVIEW_SYNTHESIS
  subtype: 3M2
diagnosis:
- name: Molecular genetic testing of CUL7, OBSL1 and CCDC8
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  presence: Biallelic pathogenic variants in CUL7, OBSL1 or CCDC8
  description: >-
    Diagnosis can be established by the characteristic prenatal-onset persistent growth deficiency with clinical
    and radiographic features and/or biallelic pathogenic variants in CUL7, OBSL1 or CCDC8. Molecular testing distinguishes
    overlapping growth disorders and assigns the subtype.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of 3-M syndrome is established in a proband with prenatal-onset persistent growth deficiency and the characteristic clinical and radiographic features and/or biallelic pathogenic variants in CCDC8, CUL7, or OBSL1 identified by molecular genetic testing."
    explanation: >-
      The GeneReviews diagnostic criterion, naming both the clinical route and the three genes.
- name: Skeletal radiography
  diagnosis_term:
    preferred_term: Skeletal radiography
    term:
      id: NCIT:C128940
      label: Radiographic Examination
  presence: Slender long bones with tall vertebral bodies, on a background of prenatal-onset growth deficiency
  description: >-
    Skeletal radiography can identify slender long bones and tall vertebral bodies with reduced anteroposterior
    dimensions. Expression varies with genotype and age: some findings become more evident during childhood, whereas
    other clinical features become less distinctive. Absence of the classic radiographic pattern should be interpreted
    with the clinical and molecular findings.
  evidence:
  - reference: PMID:11665997
    reference_title: "3-M syndrome: description of six new patients with review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "3-M syndrome can be differentiated from other types of dwarfism by clinical criteria and by the demonstration of characteristically slender long bones and foreshortened vertebral bodies."
    explanation: >-
      States the differentiating radiographic findings.
  - reference: PMID:41437277
    reference_title: "3-M syndrome: evolution of the phenotype over time."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our paper highlights how the clinical diagnosis of 3-M is easier in the first months of life, while in older children the phenotype becomes increasingly nuanced."
    explanation: >-
      The age-dependence caveat, which is why molecular testing carries more of the diagnostic weight in an older
      child.
  - reference: PMID:23517720
    reference_title: "3-M syndrome associated with growth hormone deficiency: 18 year follow-up of a patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Then, during childhood tall vertebral bodies, hip dislocation, transverse chest groove, winged scapulae and hyperextensible joints became more evident and the diagnosis of 3-M syndrome was made"
    explanation: >-
      Longitudinal case demonstrates that skeletal findings can emerge or become more evident during childhood.
    quote_role: PRIMARY_RESULT
- name: Growth surveillance
  description: >-
    Record growth and growth velocity every six to twelve months using standard growth charts.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Monitor growth every six to 12 months on standard growth charts, with special attention to growth velocity."
    explanation: GeneReviews surveillance or family-evaluation recommendation.
    quote_role: REVIEW_SYNTHESIS
- name: Musculoskeletal surveillance
  description: >-
    Assess joint hypermobility and kyphoscoliosis annually, and hip dislocation at each infant visit, particularly
    with delayed walking.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Assess for joint hypermobility and kyphoscoliosis annually. Assess for hip dislocation at each visit in infancy especially in those with delayed walking."
    explanation: GeneReviews surveillance or family-evaluation recommendation.
    quote_role: REVIEW_SYNTHESIS
- name: Adolescent aortic root assessment
  description: >-
    Consider echocardiography in adolescence to assess aortic root diameter. This is a surveillance recommendation,
    not evidence that aortic disease is universal.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consider echocardiogram in adolescence to evaluate aortic root diameter."
    explanation: GeneReviews surveillance or family-evaluation recommendation.
    quote_role: REVIEW_SYNTHESIS
- name: Evaluation of siblings at risk
  description: >-
    Evaluate siblings for short stature and consider 3-M syndrome when present. Familial variant testing informs
    diagnosis and counseling.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is appropriate to evaluate sibs of a proband for short stature and, if present, 3-M syndrome to ensure a correct diagnosis is made in affected sibs."
    explanation: GeneReviews surveillance or family-evaluation recommendation.
    quote_role: REVIEW_SYNTHESIS
treatments:
- name: Growth Hormone Therapy
  description: >-
    Pediatric endocrine assessment can guide consideration of recombinant GH in prepubertal children. Response varies,
    and GH deficiency can coexist. A retrospective 24-patient series treated 13 children for one to seven years:
    seven had a favorable response and the median height-SDS change was +0.3, with a range of -0.8 to +2.3. These
    uncontrolled data do not establish uniform benefit or its mechanism.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: somatropin
      term:
        id: NCIT:C837
        label: Somatropin
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Referral to pediatric endocrinologist for consideration of growth hormone in prepubertal children."
    explanation: >-
      GeneReviews management recommendation.
  - reference: PMID:23018678
    reference_title: "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "3-M patients typically have a modest response to GH treatment, but the mechanism is unknown."
    explanation: >-
      The source explicitly states that the mechanism underlying the typically modest response is unknown.
  - reference: PMID:40974508
    reference_title: "Long-term follow-up of growth and puberty in 3-M syndrome: effects of growth hormone therapy and response variability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall median change in height SDS was +0.3 (–0.8 to +2.3), reflecting variability in response among patients receiving treatment. A favorable response was observed in 7 out of 13 patients (54%)."
    explanation: >-
      Retrospective treated subset; no randomized comparator and no uniform efficacy assumption.
    quote_role: PRIMARY_RESULT
  target_phenotypes:
  - preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
- name: Orthopedic management
  description: >-
    Orthopedic evaluation guides management of hip dislocation, scoliosis and significant joint laxity; evaluation
    itself does not imply surgery.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Orthopedic evaluation in individuals with hip dislocation, scoliosis, and significant joint laxity is essential."
    explanation: GeneReviews management recommendation.
    quote_role: REVIEW_SYNTHESIS
- name: Surgical limb lengthening
  description: >-
    Limb lengthening may be considered as an option after specialist assessment; the cited synthesis does not provide
    controlled efficacy or complication estimates.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgical limb lengthening may also be an option."
    explanation: GeneReviews management recommendation.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Orthopedic Surgical Procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  therapeutic_modality: SURGERY
- name: Physical therapy
  description: Physical therapy supports mobility and adaptations for short stature.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical therapy, occupational therapy, and community child health services are important in ensuring necessary adaptations for short stature are put in place to maximize access to the individual's environment."
    explanation: GeneReviews management recommendation.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Occupational therapy
  description: >-
    Occupational therapy and community child-health services support access to the environment and daily activities.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical therapy, occupational therapy, and community child health services are important in ensuring necessary adaptations for short stature are put in place to maximize access to the individual's environment."
    explanation: GeneReviews management recommendation.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Occupational Therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
- name: Endocrine management of hypogonadism
  description: >-
    Monitor pubertal progression and refer gonadal dysfunction to endocrinology; spontaneous pubertal onset does
    not exclude later arrest.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Management of hypogonadism per endocrinologist."
    explanation: GeneReviews management recommendation.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:38847008
    reference_title: "Gonadal Failure in a Male With 3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Subsequently, a regression of testicular volumes, increased gonadotropin levels, and reduced (although normal) testosterone levels were observed."
    explanation: >-
      A CUL7-related case developed gonadal dysfunction after spontaneous pubertal progression; hormone and testicular
      findings support longitudinal endocrine monitoring.
- name: Urologic management of hypospadias
  description: >-
    Urology referral may be needed for hypospadias, with care adapted to the individual anatomy.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Urology referral may be needed for hypospadias."
    explanation: GeneReviews management recommendation.
    quote_role: REVIEW_SYNTHESIS
- name: Neonatal respiratory support
  description: >-
    Severe neonatal respiratory distress requires neonatal or pediatric intensive-care input and subsequent respiratory
    follow-up.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In neonates with severe respiratory distress, neonatal/pediatric intensive care team input and follow up with a pediatric respiratory physician."
    explanation: GeneReviews management recommendation.
    quote_role: REVIEW_SYNTHESIS
- name: Pregnancy care
  description: >-
    Pregnancy care should follow guidance for women with dwarfism or small stature, with attention to premature
    birth risk.
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Follow pregnancy management guidelines as for women with other forms of dwarfism or small stature to reduce the risk of premature birth."
    explanation: GeneReviews management recommendation.
    quote_role: REVIEW_SYNTHESIS
- name: Genetic Counseling
  description: >-
    Autosomal recessive counseling: a 25% recurrence risk for each sib once both parents are known carriers, with
    carrier testing and prenatal or preimplantation genetic testing possible after the familial variants are identified.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier"
    explanation: >-
      GeneReviews genetic counseling guidance.
  - reference: PMID:20301654
    reference_title: "3-M Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the 3-M syndrome-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible."
    explanation: Defines prerequisites for reproductive and family testing.
    quote_role: REVIEW_SYNTHESIS
- name: Recombinant IGF1 therapy, investigational reported use
  description: >-
    A single CUL7-related case received recombinant IGF1 for presumed GH insensitivity. Height improvement was minimal
    and accelerated weight gain, morbid obesity and associated complications developed; therapy was discontinued.
    This report does not support routine use.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Mecasermin
      term:
        id: NCIT:C2262
        label: Mecasermin
  evidence:
  - reference: PMID:32924381
    reference_title: "Effect of recombinant human insulin-like growth factor 1 therapy in a child with 3-M syndrome-1 with CUL7 gene mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case highlights the novel use of rhIGF-1 therapy on a child with 3-M syndrome-1 with minimal height benefit but accelerated weight gain"
    explanation: >-
      Single-patient experience with limited benefit and adverse outcomes; not a recommendation.
    quote_role: PRIMARY_RESULT
animal_models:
- name: Cartilage-specific Cul7 knockout mouse
  species: Mouse
  genotype: Cul7fl/fl;Col2a1-CreERT2
  publication: PMID:38367951
  description: >-
    A conditional, cartilage-restricted Cul7 knockout that survives past birth, unlike the constitutive null, and
    so allows the growth plate to be studied directly.
  modeled_mechanisms:
  - target: Reduced Growth Plate Proliferative-zone Cellularity
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Models reduced proliferative-zone cellularity and abnormal skeletal growth after cartilage-specific Cul7 deletion.
    limitations: >-
      Conditional, tissue-restricted CUL7 knockout, compared with Cul7fl/+;Col2a1-CreERT2 mice. It does not establish
      human growth-plate histology, a direct proliferation-rate defect, or equivalent mechanisms for OBSL1 and CCDC8.
    readouts:
    - name: Proliferative-zone chondrocyte number
      target: Reduced Growth Plate Proliferative-zone Cellularity
      direction: DECREASED
      interpretation: >-
        Histological cell count, rather than a directly assayed proliferation rate.
      evidence:
      - reference: PMID:38367951
        reference_title: "Longitudinal skeletal growth and growth plate morphological characteristics of chondro-tissue specific CUL7 knockout mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "decreased number of cells in the proliferation zone"
        explanation: >-
          The measured reduction in proliferative-zone cellularity.
    - name: Limb length
      target: Reduced Growth Plate Proliferative-zone Cellularity
      direction: DECREASED
      interpretation: >-
        Associated skeletal-growth phenotype after cartilage-specific Cul7 deletion.
      evidence:
      - reference: PMID:38367951
        reference_title: "Longitudinal skeletal growth and growth plate morphological characteristics of chondro-tissue specific CUL7 knockout mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "mice had abnormally short and deformed limbs"
        explanation: >-
          The gross skeletal readout of the model.
    evidence:
    - reference: PMID:38367951
      reference_title: "Longitudinal skeletal growth and growth plate morphological characteristics of chondro-tissue specific CUL7 knockout mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The knockout of Cul7 gene may affect both the proliferation of chondrocytes and the endochondral osteogenesis"
      explanation: >-
        Supports treating this model as informative for the growth-plate node.
- name: Ccdc8 knockout mouse
  species: Mouse
  genotype: Ccdc8 null
  publication: PMID:31343991
  description: >-
    Constitutive Ccdc8 deletion produces placental abnormalities together with intrauterine growth restriction;
    additional fetal tissue defects may contribute.
  modeled_mechanisms:
  - target: Abnormal Placental Development
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Establishes that deleting a 3-M gene impairs trophoblast migration and placental development and produces
      intrauterine growth restriction.
    limitations: >-
      Constitutive deletion causes perinatal lethality in mice, whereas human CCDC8-related disease permits survival
      into adulthood. The model cannot directly address human postnatal growth or establish relative severity among
      human genotypes.
    readouts:
    - name: Fetal growth
      target: Abnormal Placental Development
      direction: DECREASED
      interpretation: >-
        Fetal growth restriction accompanying placental abnormalities in the knockout.
      evidence:
      - reference: PMID:31343991
        reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "resulting in intrauterine growth restriction and perinatal lethality"
        explanation: >-
          The measured growth outcome in the knockout.
    evidence:
    - reference: PMID:31343991
      reference_title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Deletion of Ccdc8 in mice impaired trophoblast migration and placental development"
      explanation: >-
        Supports treating this model as informative for the placental node.
- name: Constitutive Cul7 (p185) knockout mouse
  species: Mouse
  genotype: Cul7 (p185) null
  publication: PMID:12904573
  description: >-
    The original Cul7 null, runted and perinatally lethal from respiratory distress, with defective trophoblast
    differentiation and abnormal placental vasculature.
  modeled_mechanisms:
  - target: Abnormal Placental Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Converges on the same placental trophoblast defect from a different 3-M
      gene.
    limitations: >-
      Perinatally lethal, so it does not model the viable human disease; the reported emphasis is vascular morphogenesis
      rather than the migration defect later shown for the 3-M ligase.
    readouts:
    - name: Placental trophoblast differentiation
      target: Abnormal Placental Development
      direction: ALTERED
      interpretation: >-
        Histological correlate of the placental node.
      evidence:
      - reference: PMID:12904573
        reference_title: "Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "placentas show defects in the differentiation of the trophoblast lineage with an abnormal vascular structure"
        explanation: >-
          The measured placental phenotype.
    evidence:
    - reference: PMID:12904573
      reference_title: "Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "embryos are runted and die immediately after birth because of respiratory distress"
      explanation: >-
        Supports treating this model as informative for prenatal growth failure, while its perinatal lethality is
        the limitation recorded above.
- name: OBSL1 frameshift sheep with brachygnathia, cardiomegaly and renal hypoplasia
  species: Sheep
  background: Australian Poll Merino/Merino flock
  genotype: Homozygous OBSL1 c.1716delC, predicted p.(Val573Trpfs*119)
  publication: PMID:32933480
  description: >-
    A naturally occurring recessive syndrome with an OBSL1 frameshift that segregated in seven affected lambs and
    six obligate carriers. The authors propose an ovine model of 3-M syndrome type 2. Affected lambs are stillborn
    with short stature and skeletal abnormalities, plus cardiac and renal defects that extend beyond the usual human
    phenotype.
  modeled_mechanisms:
  - target: Dysfunction of a 3-M Complex Component
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      A segregating predicted truncating OBSL1 variant provides a naturally occurring genetic counterpart to human
      OBSL1-related disease.
    limitations: >-
      Affected lambs are stillborn, so this is not a viable adult model or a model of postnatal growth. The study
      establishes segregation and predicts protein truncation; it does not measure OBSL1 protein loss, altered complex
      assembly, LL5-beta regulation or growth-factor responses. The severe cardiac and renal phenotype should not
      be transferred to human 3-M syndrome.
    readouts:
    - name: OBSL1 genotype segregation
      target: Dysfunction of a 3-M Complex Component
      direction: ALTERED
      interpretation: All seven affected lambs were homozygous for the deletion; obligate carriers were heterozygous.
      evidence:
      - reference: PMID:32933480
        reference_title: "Molecular basis of a new ovine model for human 3M syndrome-2."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        quote_role: PRIMARY_RESULT
        snippet: "All seven affected animals were homozygous for the deletion, six obligate carrier animals were heterozygous and two phenotypically unaffected and one unrelated control animals were homozygous wildtype"
        explanation: >-
          Segregation supports a likely causal OBSL1 frameshift in this flock; protein function and complex assembly
          were not directly assayed.
    evidence:
    - reference: PMID:32933480
      reference_title: "Molecular basis of a new ovine model for human 3M syndrome-2."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "All seven affected animals were homozygous for the deletion, six obligate carrier animals were heterozygous and two phenotypically unaffected and one unrelated control animals were homozygous wildtype"
      explanation: >-
        Segregation supports a likely causal OBSL1 frameshift in this flock; protein function and complex assembly
        were not directly assayed.
  evidence:
  - reference: PMID:32933480
    reference_title: "Molecular basis of a new ovine model for human 3M syndrome-2."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "Affected lambs are stillborn with various congenital defects as reflected in the name of the disease, as well as short stature, a short and broad cranium, a small thoracic cavity, thin ribs and brachysternum."
    explanation: >-
      The study describes the established phenotype of the source flock, including its lethal course.
references:
- reference: PMID:20301654
  title: "3-M Syndrome."
  tags:
  - GeneReviews
- reference: PMID:16142236
  title: "Identification of mutations in CUL7 in 3-M syndrome."
- reference: PMID:19481195
  title: "The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1."
- reference: PMID:21737058
  title: "Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth."
- reference: PMID:23018678
  title: "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling."
- reference: PMID:22624670
  title: "Exploring the spectrum of 3-M syndrome, a primordial short stature disorder of disrupted ubiquitination."
- reference: PMID:11665997
  title: "3-M syndrome: description of six new patients with review of the literature."
- reference: PMID:41437277
  title: "3-M syndrome: evolution of the phenotype over time."
- reference: PMID:31343991
  title: "Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development."
- reference: PMID:38367951
  title: "Longitudinal skeletal growth and growth plate morphological characteristics of chondro-tissue specific CUL7 knockout mice."
- reference: PMID:12904573
  title: "Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis."
- reference: PMID:17675530
  title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
- reference: PMID:24148222
  title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
- reference: PMID:24793695
  title: "The 3M complex maintains microtubule and genome integrity."
- reference: PMID:40974508
  title: "Long-term follow-up of growth and puberty in 3-M syndrome: effects of growth hormone therapy and response variability."
- reference: PMID:23517720
  title: "3-M syndrome associated with growth hormone deficiency: 18 year follow-up of a patient."
- reference: PMID:32924381
  title: "Effect of recombinant human insulin-like growth factor 1 therapy in a child with 3-M syndrome-1 with CUL7 gene mutation."
- reference: PMID:38847008
  title: "Gonadal Failure in a Male With 3-M Syndrome."
- reference: PMID:32933480
  title: "Molecular basis of a new ovine model for human 3M syndrome-2."
histopathology:
- name: Reduced bronchial cartilaginous lamina
  subtype: 3M1
  description: >-
    In one affected 26-week CUL7 fetus, compared with an unaffected fetus, medium and large bronchi had small, insufficiently
    developed cartilaginous laminae. Alveolar tissues showed no obvious abnormality. This observation supports a
    possible airway-development contribution to neonatal respiratory distress without establishing a universal mechanism.
  evidence:
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "the amount of cartilaginous lamina of the medium and large bronchi was small and the cartilaginous lamina insufficiently developed"
    explanation: >-
      Single affected fetal specimen; frequency and causal contribution to liveborn respiratory distress remain
      uncertain.
- name: Abnormal chorionic villi and intervillous spaces
  subtype: 3M1
  description: >-
    The same affected fetal placenta had increased chorionic villi with numerous syncytial knots and constricted
    intervillous lacunae. Trophoblast giant-cell number was normal, contrasting with aspects of the constitutive
    mouse knockout phenotype.
  evidence:
  - reference: PMID:17675530
    reference_title: "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "a marked increase in the number of chorionic villi with numerous syncytial knots and intervillous lacuna constriction was observed"
    explanation: >-
      Human fetal histology provides a limited clinical counterpart to the mouse placental models.
experimental_models:
- experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  cell_source: Patient-derived skin fibroblasts with molecularly confirmed 3-M syndrome
  culture_system: Cultured fibroblast monolayers
  name: Patient fibroblasts for genotype-specific growth-factor responses
  publication: PMID:23018678
  description: >-
    Patient-derived fibroblasts representing CUL7, OBSL1 and CCDC8 defects were used to compare GH- and IGF1-stimulated
    intracellular signaling. The observed response depends on the mutated gene and the assayed pathway.
  modeled_mechanisms:
  - target: Reduced Cellular Response to Growth Hormone
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Provides the gh-stimulated stat5b and mapk activation readout in patient-derived cultured cells.
    limitations: >-
      Response differs by genotype: OBSL1 and CCDC8 cells had reduced GH responses, whereas CUL7 and OBSL1 cells
      had reduced early IGF1 responses. These assays do not establish the cause of variable clinical GH efficacy.
    readouts:
    - name: GH-stimulated STAT5b and MAPK activation
      target: Reduced Cellular Response to Growth Hormone
      direction: DECREASED
      interpretation: >-
        Cellular measurement under the study conditions; it does not directly establish human growth-plate physiology.
      evidence:
      - reference: PMID:23018678
        reference_title: "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "activation of STAT5b and MAPK in response to GH was normal in CUL7(-/-) cells but reduced in OBSL1(-/-) and CCDC8(-/-) cells compared with controls."
        explanation: >-
          Patient fibroblasts show genotype-dependent GH responses; CUL7-deficient cells retained the measured response.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:23018678
      reference_title: "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "activation of STAT5b and MAPK in response to GH was normal in CUL7(-/-) cells but reduced in OBSL1(-/-) and CCDC8(-/-) cells compared with controls."
      explanation: >-
        Patient fibroblasts show genotype-dependent GH responses; CUL7-deficient cells retained the measured response.
      quote_role: PRIMARY_RESULT
  - target: Reduced Cellular Response to IGF1
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Provides the igf1-stimulated akt activation readout in patient-derived cultured cells.
    limitations: >-
      Response differs by genotype: OBSL1 and CCDC8 cells had reduced GH responses, whereas CUL7 and OBSL1 cells
      had reduced early IGF1 responses. These assays do not establish the cause of variable clinical GH efficacy.
    readouts:
    - name: IGF1-stimulated AKT activation
      target: Reduced Cellular Response to IGF1
      direction: DECREASED
      interpretation: >-
        Cellular measurement under the study conditions; it does not directly establish human growth-plate physiology.
      evidence:
      - reference: PMID:23018678
        reference_title: "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Activation of AKT to IGF1 was reduced in CUL7(-/-) and OBSL1(-/-) cells at 5 min post-stimulation but normal in CCDC8(-/-) cells."
        explanation: Specifies the cellular endpoint, stimulation time and genotypes tested.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:23018678
      reference_title: "Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Activation of AKT to IGF1 was reduced in CUL7(-/-) and OBSL1(-/-) cells at 5 min post-stimulation but normal in CCDC8(-/-) cells."
      explanation: Specifies the cellular endpoint, stimulation time and genotypes tested.
      quote_role: PRIMARY_RESULT
- experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  cell_source: Patient-derived skin fibroblasts with molecularly confirmed 3-M syndrome
  culture_system: Cultured fibroblast monolayers
  name: Patient fibroblasts for IGF2 and H19 expression and IGF-II secretion
  publication: PMID:24148222
  description: >-
    Forearm fibroblasts from four prepubertal patients, one with CUL7, two with OBSL1 and one with CCDC8 variants,
    were compared with three control lines derived from skin tags. Quantitative PCR measured RNA abundance and ELISA
    measured IGF-II in conditioned medium. Assayed H19 and IGF2 methylation regions did not differ.
  modeled_mechanisms:
  - target: Reduced IGF2 Expression
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Provides the igf2 rna abundance readout in patient-derived cultured cells.
    limitations: >-
      Four patient lines were compared with three controls. Cultured skin fibroblasts do not directly model placental
      or growth-plate tissue, and no causal rescue of human growth was demonstrated.
    readouts:
    - name: IGF2 RNA abundance
      target: Reduced IGF2 Expression
      direction: DECREASED
      interpretation: >-
        Cellular measurement under the study conditions; it does not directly establish human growth-plate physiology.
      evidence:
      - reference: PMID:24148222
        reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."
        explanation: >-
          Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three
          control
          lines.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:24148222
      reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."
      explanation: >-
        Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three
        control
        lines.
      quote_role: PRIMARY_RESULT
  - target: Increased H19 Expression
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Provides the h19 rna abundance readout in patient-derived cultured cells.
    limitations: >-
      Four patient lines were compared with three controls. Cultured skin fibroblasts do not directly model placental
      or growth-plate tissue, and no causal rescue of human growth was demonstrated.
    readouts:
    - name: H19 RNA abundance
      target: Increased H19 Expression
      direction: INCREASED
      interpretation: >-
        Cellular measurement under the study conditions; it does not directly establish human growth-plate physiology.
      evidence:
      - reference: PMID:24148222
        reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."
        explanation: >-
          Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three
          control
          lines.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:24148222
      reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "QRT-PCR confirmed upregulation of H19 (P<0.001) and downregulation of IGF2 (P<0.001)."
      explanation: >-
        Gene-expression measurements in four patient fibroblast lines representing the three genotypes and three
        control
        lines.
      quote_role: PRIMARY_RESULT
  - target: Reduced IGF-II Secretion
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Provides the igf-ii in conditioned medium readout in patient-derived cultured cells.
    limitations: >-
      Four patient lines were compared with three controls. Cultured skin fibroblasts do not directly model placental
      or growth-plate tissue, and no causal rescue of human growth was demonstrated.
    readouts:
    - name: IGF-II in conditioned medium
      target: Reduced IGF-II Secretion
      direction: DECREASED
      interpretation: >-
        Cellular measurement under the study conditions; it does not directly establish human growth-plate physiology.
      evidence:
      - reference: PMID:24148222
        reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Levels of IGF-II secreted into conditioned cell culture medium were higher for control fibroblasts than those for 3-M fibroblasts (10.2±2.9 vs 0.6±0.9 ng/ml, P<0.01)."
        explanation: Conditioned-medium ELISA documents reduced secretion in cultured patient fibroblasts.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:24148222
      reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Levels of IGF-II secreted into conditioned cell culture medium were higher for control fibroblasts than those for 3-M fibroblasts (10.2±2.9 vs 0.6±0.9 ng/ml, P<0.01)."
      explanation: Conditioned-medium ELISA documents reduced secretion in cultured patient fibroblasts.
      quote_role: PRIMARY_RESULT
  evidence:
  - reference: PMID:24148222
    reference_title: "3-M syndrome: a growth disorder associated with IGF2 silencing."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Skin fibroblast cell lines were derived from four 3-M syndrome patients and three control subjects."
    explanation: >-
      The Methods specify the biological sampling units; technical replicate wells are not additional patients.
- experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  cell_source: Patient-derived skin fibroblasts with molecularly confirmed 3-M syndrome
  culture_system: Cultured fibroblast monolayers
  name: CUL7-mutant patient fibroblasts for ploidy assessment
  publication: PMID:24793695
  description: >-
    Two patient skin fibroblast lines carrying CUL7 variants were compared with normal foreskin and lung fibroblast
    cell lines. Increased ploidy provided a patient-derived correlate of cell-division defects studied separately
    in depleted experimental cell lines.
  modeled_mechanisms:
  - target: Defective Cytokinesis
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Provides the tetraploid-cell proportion readout in patient-derived cultured cells.
    limitations: >-
      Ploidy is an indirect correlate of cell-division failure. The comparator lines differ in tissue source and
      passage, and the reported wild-type CUL7 rescue was performed in CUL7-depleted experimental cells rather than
      these patient fibroblasts.
    readouts:
    - name: Tetraploid-cell proportion
      target: Defective Cytokinesis
      direction: INCREASED
      interpretation: >-
        Cellular measurement under the study conditions; it does not directly establish human growth-plate physiology.
      evidence:
      - reference: PMID:24793695
        reference_title: "The 3M complex maintains microtubule and genome integrity."
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: "These two lines of 3M fibroblast cells contained 8.8% and 6.4% of tetraploid cells"
        explanation: >-
          Patient-line ploidy measurement. Control cell lines differed in tissue origin and passage; the result
          is not a direct live-cell assay of cytokinesis in patients.
    evidence:
    - reference: PMID:24793695
      reference_title: "The 3M complex maintains microtubule and genome integrity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: "These two lines of 3M fibroblast cells contained 8.8% and 6.4% of tetraploid cells"
      explanation: >-
        Patient-line ploidy measurement. Control cell lines differed in tissue origin and passage; the result is
        not a direct live-cell assay of cytokinesis in patients.

📚

References & Deep Research

References

19

PMID:20301654

3-M Syndrome.

No top-level findings curated for this source.

PMID:16142236

Identification of mutations in CUL7 in 3-M syndrome.

No top-level findings curated for this source.

PMID:19481195

The primordial growth disorder 3-M syndrome connects ubiquitination to the cytoskeletal adaptor OBSL1.

No top-level findings curated for this source.

PMID:21737058

Exome sequencing identifies CCDC8 mutations in 3-M syndrome, suggesting that CCDC8 contributes in a pathway with CUL7 and OBSL1 to control human growth.

No top-level findings curated for this source.

PMID:23018678

Mutations in CUL7, OBSL1 and CCDC8 in 3-M syndrome lead to disordered growth factor signalling.

No top-level findings curated for this source.

PMID:22624670

Exploring the spectrum of 3-M syndrome, a primordial short stature disorder of disrupted ubiquitination.

No top-level findings curated for this source.

PMID:11665997

3-M syndrome: description of six new patients with review of the literature.

No top-level findings curated for this source.

PMID:41437277

3-M syndrome: evolution of the phenotype over time.

No top-level findings curated for this source.

PMID:31343991

Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development.

No top-level findings curated for this source.

PMID:38367951

Longitudinal skeletal growth and growth plate morphological characteristics of chondro-tissue specific CUL7 knockout mice.

No top-level findings curated for this source.

PMID:12904573

Targeted disruption of p185/Cul7 gene results in abnormal vascular morphogenesis.

No top-level findings curated for this source.

PMID:17675530

Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts: new population isolate in Asia.

No top-level findings curated for this source.

PMID:24148222

3-M syndrome: a growth disorder associated with IGF2 silencing.

No top-level findings curated for this source.

PMID:24793695

The 3M complex maintains microtubule and genome integrity.

No top-level findings curated for this source.

PMID:40974508

Long-term follow-up of growth and puberty in 3-M syndrome: effects of growth hormone therapy and response variability.

No top-level findings curated for this source.

PMID:23517720

3-M syndrome associated with growth hormone deficiency: 18 year follow-up of a patient.

No top-level findings curated for this source.

PMID:32924381

Effect of recombinant human insulin-like growth factor 1 therapy in a child with 3-M syndrome-1 with CUL7 gene mutation.

No top-level findings curated for this source.

PMID:38847008

Gonadal Failure in a Male With 3-M Syndrome.

No top-level findings curated for this source.

PMID:32933480

Molecular basis of a new ovine model for human 3M syndrome-2.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review 3-M syndrome mechanisms, clinical spectrum and management · 2026-09-21T01:36:47Z · View source

Compared the complete matching deep-research report and citation audit with the disorder entry and primary literature. Rebuilt the mechanism graph as 15 atomic nodes, separating membrane LL5-beta targeting, cell migration and placental findings from genotype-specific GH/IGF1 responses, IGF2/H19 expression, microtubule/mitotic defects and cartilage-specific mouse findings. Removed unsupported linear causal chains, universal catalytic loss, complete penetrance, severity ranking of sparse CCDC8 cases, and radiographic age claims. Expanded to 59 phenotypes with source-specific counts, neonatal respiratory distress, developmental delay, endocrine findings and fetal histology; mined all four GeneReviews clinical/testing/management/counseling domains and added variable GH and reported IGF1 outcomes. Independent source review confirmed mechanism scope and model limitations. Schema, live ontology and reference validation passed with 151 exact snippets; GeneReviews baseline and coarse-phenotype checks passed. New and refreshed references were generated only through just fetch-reference; no manual cache editing or dataset-accession blob access.

Create: 3-M Syndrome · 2026-08-27T04:18:03Z · View source

New entry for ISDS Nosology 2023 group 21 rows NOS 21-0010/0020/0030, which had no dismech coverage. Deep research: claude_code provider (research/3-M_Syndrome-deep-research-claude_code.md); its reference validation reported 19/19 references resolved, 2/2 quoted claims verified, 0 off topic. NEC preflight returned SKIP because MONDO records no causal gene for MONDO:0007477, so the manual check was used instead: the report's top genes are CUL7/OBSL1/CCDC8 and its OMIM numbers are 273750/612921/614205, matching the three nosology rows exactly. The report's HGNC identifiers were wrong (it gave HGNC:16290/15738/17086, which are TRIM33, an unassigned id, and CSTF2T); all three were re-resolved against the HGNC REST API to hgnc:21024, hgnc:29092 and hgnc:25367 before use. GeneReviews (PMID:20301654) was fetched and used as the phenotype baseline; every Clinical Characteristics feature in its abstract is curated. Pathophysiology is a six-node chain from ligase-subunit loss through failed membrane assembly of the 3-M complex to the placental and growth-plate arms, with three animal models linked via modeled_mechanisms. Lumping: one entry covering all three genes, with the nosology's per-gene split preserved as has_subtypes bound to MONDO:0010117/0013039/0013627. Validation: schema clean, term validation passed, 60/60 snippets verified against cached references, entity refs and duplicate-key checks clean.

Claude Code ▸

3-M Syndrome: Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 20 citations 2026-08-27T01:45:22.080316

3-M Syndrome: Comprehensive Research Report

1. Disease Information

Overview. 3-M syndrome (also written "3M syndrome," "Miller-McKusick-Malvaux syndrome," "Le Merrer syndrome," or "Gloomy face syndrome") is a rare autosomal recessive primordial growth disorder — meaning growth restriction begins prenatally and persists throughout life without a "catch-up" phase — characterized by severe pre- and postnatal growth deficiency, a distinctive facial gestalt, characteristic skeletal/radiographic findings, and normal intelligence. The name derives from the surnames of the three physicians (Miller, McKusick, Malvaux) who first described it in 1975.

Key identifiers: - OMIM: 3M syndrome 1 (#273750, CUL7), 3M syndrome 2 (#612921, OBSL1), 3M syndrome 3 (#614205, CCDC8) OMIM #273750; OMIM #612921; OMIM #614205 - Orphanet: ORPHA2616 (Orphanet: 3M syndrome) - MONDO: MONDO:0007477 (3M syndrome 1); related MONDO terms exist per subtype - Disease Ontology: DOID:0060241 - GeneReviews: NBK1481 (Cormier-Daire, Huber, et al., updated periodically) - GTR/MeSH/ICD: Listed under primordial dwarfism / short stature syndromes; no dedicated ICD-10-CM code beyond the general short-stature syndrome category

Synonyms: 3M syndrome; Miller-McKusick-Malvaux syndrome; Le Merrer syndrome; Gloomy face syndrome (historical, now discouraged); Dolichospondylic dysplasia; Yakut short stature syndrome (population-specific CUL7 founder-variant form).

Data derivation: Information is drawn predominantly from aggregated case-series/cohort literature (fewer than ~250 molecularly confirmed cases reported worldwide as of 2025) rather than large-scale EHR/registry data, reflecting the disorder's rarity. GeneReviews and the recent 2025 natural-history literature review (217 pooled cases from 36 publications) are the most authoritative aggregate sources.

2. Etiology

Disease causal factors — genetic. 3-M syndrome is caused by biallelic (homozygous or compound heterozygous) loss-of-function variants in one of three genes encoding components of a single molecular complex:

Subtype	OMIM	Gene	Locus	Approx. proportion of cases
3M1	#273750	CUL7 (Cullin-7)	6p21.1	~65–75%
3M2	#612921	OBSL1 (Obscurin-like 1)	2q35	~28–34%
3M3	#614205	CCDC8 (Coiled-coil domain containing 8)	19q13.32	~1–5%

Approximately 1% of clinically diagnosed cases remain molecularly unresolved, suggesting additional causative genes or loci may exist (GeneReviews NBK1481).

CUL7 variants: predominance of null variants (nonsense, splice-site; missense also frequent); ~50% of pathogenic variants localize to the cullin domain critical for ROC1 anchoring.
OBSL1 variants: most pathogenic variants occur within the first 8 exons, affecting all known isoforms, predominantly loss-of-function.
CCDC8: a single-exon gene; pathogenic variants lead to truncation and loss of function.

Founder variants (population-specific risk factors): - Yakut population (Siberia): CUL7 c.4581dupT (also reported as 4582_4583insT), described by Maksimova et al. 2007, associated with a distinctive phenotype of high neonatal respiratory distress but comparatively few bone abnormalities (PMC2652813). - Maghrebian/Tunisian population: CUL7 c.4451_4452delTG. - Turkish population: OBSL1 c.1273dupA (emerging founder variant).

Risk factors: - Genetic: Consanguinity substantially raises risk given the autosomal recessive inheritance and regional founder alleles; carrier parents (heterozygotes) are asymptomatic. - Environmental: No environmental, toxin, infectious, or lifestyle risk factors have been identified — this is a purely monogenic Mendelian disorder. - Modifier genes: None formally established, though phenotypic variability (e.g., milder stature in CCDC8-related disease vs. more severe in CUL7-related disease) suggests gene-specific and possibly allele-specific modulation of severity.

Protective factors: None described; this is a fully penetrant recessive disorder once biallelic pathogenic variants are present.

Gene-environment interactions: Not applicable/not reported — no environmental modifiers of penetrance or expressivity have been documented in the literature.

3. Phenotypes

Growth phenotype

Severe pre- and postnatal growth deficiency: final adult height typically ~5 SD below the mean (range roughly 115–150 cm in adults). Birth length typically 40–42 cm with normal head circumference for gestational age (giving the appearance of relative macrocephaly).
No catch-up growth occurs; short stature is proportionate. HPO: HP:0004322 (Short stature), HP:0001511 (Intrauterine growth retardation).

Craniofacial features

Characteristic facies including: relative macrocephaly (HP:0004482 / HP:0000256 macrocephaly-adjacent terms), dolichocephaly (HP:0000268), triangular face (HP:0000325), midface retrusion (HP:0011800), thick eyebrows (HP:0000574), fleshy/bulbous nasal tip (HP:0000455-adjacent), long philtrum (HP:0000343), thick vermilion of upper and lower lips (HP:0012471), pointed chin (HP:0000307). Infants may show facial nevus simplex and infraorbital fullness that fade with age. Facial appearance is most diagnostic in infancy and becomes progressively subtler through childhood into adolescence, per a 2025 natural-history review of 217 cases (Ital J Pediatr, PMID 41437277, DOI 10.1186/s13052-025-02172-8).

Musculoskeletal features

Short broad neck, prominent trapezii, pectus carinatum/excavatum (HP:0000768/HP:0000767), short thorax, square shoulders, winged scapulae, thoracic kyphoscoliosis (HP:0002751), hyperlordosis (HP:0002938), spina bifida occulta, clinodactyly of the fifth finger (HP:0004209), joint hypermobility (HP:0001382), hip dislocation, prominent heels, pes planus (HP:0001763).

Radiographic (skeletal) hallmark features

Slender long bones with diaphyseal constriction and flared metaphyses — the primary distinguishing radiologic sign.
Tall vertebral bodies with reduced anteroposterior and transverse diameters, especially lumbar.
Elevated metacarpal and vertebral indices.
Small pelvic bones. These become "increasingly vague" with age, per the 2025 natural-history review, so radiographic diagnosis is most reliable in infancy.

Neurodevelopmental

Normal intelligence is a defining and diagnostically important feature that distinguishes 3-M syndrome from many other severe short-stature/primordial-dwarfism syndromes (e.g., Seckel syndrome, microcephalic primordial dwarfism).

Endocrine/reproductive

Males may have hypogonadism and occasionally hypospadias (HP:0000047); a 2024 JCEM Case Reports paper documented a CUL7-variant male with bifid scrotum and perineal hypospadias at birth, spontaneous but incomplete pubertal maturation, and progressive gonadal failure in adolescence (declining testicular volume, rising gonadotropins, low-normal testosterone) (PMID 38847008, PMC11154130). Female gonadal function appears normal. Endocrine (thyroid, adrenal) function is otherwise generally normal.

Cardiac

Aortic root dilatation reported in some individuals — a rationale for periodic echocardiographic surveillance.

Respiratory

Some neonates, particularly in the Yakut founder-variant population, experience significant neonatal respiratory distress (~41% in that population), sometimes requiring NICU care.

Quality of life

Not formally quantified with standardized instruments (EQ-5D/SF-36) in the literature reviewed; qualitatively, impact centers on short-stature-related psychosocial and functional issues (adaptive equipment needs, orthopedic complications) rather than cognitive/behavioral burden, since intelligence and daily function are largely preserved.

4. Genetic/Molecular Information

Causal genes: CUL7 (HGNC:16290, OMIM 609577), OBSL1 (HGNC:15738, OMIM 610991), CCDC8 (HGNC:17086, OMIM *614145).

Pathogenic variant classification: Per ACMG/AMP framework, disease-causing alleles are classified as pathogenic/likely pathogenic biallelic loss-of-function or damaging missense variants; heterozygous carriers are unaffected. ClinVar/ClinGen entries exist for known recurrent and founder variants.

Variant types: - Nonsense, frameshift, and canonical splice-site variants predominate for CUL7 and OBSL1 (loss-of-function mechanism). - Missense variants also occur in CUL7, frequently clustering in the cullin domain required for ROC1 (RBX1) anchoring within the SCF-like complex. - CCDC8, being single-exon, is disrupted almost exclusively by truncating variants causing loss of function.

Allele frequency: No individual pathogenic variant reaches appreciable frequency in general population databases (gnomAD) outside specific founder populations (Yakut, Maghrebian/Tunisian, Turkish), consistent with an ultra-rare recessive disorder.

Origin: Germline, biallelic — not somatic; both alleles inherited from heterozygous, unaffected parents (or occasionally uniparental disomy/de novo events, though these are not prominently reported for this condition).

Functional consequence — molecular mechanism: CUL7 is a member of the Cullin family and forms the scaffold of an SCF-like (Skp1–Cullin–F-box) E3 ubiquitin ligase complex localized to the Golgi apparatus. This complex: - Physically interacts with OBSL1 and CCDC8 to form the "3-M E3 complex," which regulates microtubule dynamics and ubiquitinates the membrane-associated protein LL5β, impacting cell migration and cytoskeletal regulation (Hanson et al. 2009, Am J Hum Genet, PMC2694976; PMID 19481195). - Is implicated in proteasomal degradation of IRS-1 (insulin receptor substrate-1) and cyclin D1. CUL7 interacts with IRS-1, a downstream signaling node shared by insulin, IGF-1, and GH receptor pathways. Loss of CUL7 function leads to IRS-1 accumulation (impaired proteasomal turnover), and downstream reduced IGF-1-mediated activation of Akt and reduced cell proliferation (Endocrine Abstracts EA0021P232). - Loss of CUL7 also reduces OBSL1 transcription, tying the three genes into a single interdependent pathway — consistent with all three genes producing a convergent, largely indistinguishable phenotype (CUL7- and OBSL1-related disease are "clinically and radiographically indistinguishable," per GeneReviews, though CUL7-related disease tends to produce shorter final stature). - A separate mechanistic axis: 3-M fibroblasts show an epigenetic gene-expression signature of reduced IGF2 expression and increased H19 expression, resembling the imprinting profile of Silver-Russell syndrome, with markedly reduced IGF-II secretion in conditioned culture medium (10.2±2.9 ng/mL control vs. 0.6±0.9 ng/mL 3-M fibroblasts, P<0.01) — implicating IGF2 silencing as a contributing, gene-network-level (not primary genetic-imprinting) mechanism (Meyer et al. 2013, Endocr Connect, PMID 24148222, PMC3847915).

Modifier genes: None formally established; phenotype-genotype correlation is largely gene-specific (CUL7 > OBSL1 > CCDC8 severity gradient) rather than driven by known secondary modifiers.

Epigenetic information: The IGF2/H19 imprinting-like expression signature above is the principal epigenetic finding; it appears to be a downstream transcriptional consequence of E3-complex disruption rather than a primary imprinting defect.

Chromosomal abnormalities: 3-M syndrome is not caused by large structural chromosomal rearrangements; it is a single-gene (biallelic small-variant) disorder. No characteristic CNV/translocation etiology has been reported.

5. Environmental Information

3-M syndrome is a monogenic Mendelian disorder with no identified environmental, toxin, infectious, or lifestyle contributing factors. It is not associated with teratogen exposure, maternal illness, or infectious triggers. The only population-level "risk factor" beyond genetics is consanguinity, which increases the probability of biallelic inheritance of a rare recessive allele, and geographic/ethnic founder-variant enrichment (Yakut, Maghrebian, Turkish populations).

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

Molecular trigger: Biallelic loss-of-function variant in CUL7, OBSL1, or CCDC8 → loss of function of one component of the Golgi-localized 3-M E3 ubiquitin ligase complex.
Complex disruption: CUL7, OBSL1, and CCDC8 normally physically interact to form the joint 3-M E3 complex, which is critical for microtubule regulation and ubiquitination of the membrane-associated protein LL5β (cell migration regulator). Loss of any one component destabilizes the complex.
Impaired proteostasis of growth-signaling intermediates: Failure of ubiquitin-mediated proteasomal degradation of IRS-1 (and cyclin D1) → IRS-1 accumulation.
Blunted IGF-1/insulin/GH signal transduction: Because IRS-1 is a shared downstream node of insulin, IGF-1, and GH receptor pathways, its dysregulated turnover produces reduced IGF-1-mediated Akt activation and reduced cellular proliferative response to growth-factor stimulation.
Cell-cycle/cytoskeletal defects: Mitotic and cytokinesis abnormalities from loss of CUL7 function are proposed contributors to short stature; reduced OBSL1 transcription follows loss of CUL7, reinforcing pathway interdependence.
Epigenetic-level convergence: A gene-expression signature of reduced IGF2 and elevated H19 (Silver-Russell-like) further suppresses IGF-II bioavailability, compounding the growth-signaling deficit.
Tissue-level consequence — growth plate dysfunction: Cartilage-specific Cul7 knockout mice show abnormally short/deformed limbs, thickened growth plates, disorganized chondrocyte columns, decreased proliferative-zone cell numbers, and disordered trabecular bone at the metaphysis — implicating both chondrocyte proliferation defects and disrupted endochondral ossification as the proximate tissue mechanism of skeletal growth failure (Longitudinal skeletal growth study, PMID 38367951, ScienceDirect).
Organism-level phenotype: Severe proportionate pre-/postnatal growth restriction, characteristic facial dysmorphism, skeletal (long-bone/vertebral) abnormalities, and (in a subset) gonadal, cardiac, and respiratory involvement, with sparing of cognitive development.

Molecular pathways involved: Ubiquitin-proteasome system (SCF/Cullin-RING E3 ligase pathway); insulin/IGF-1/GH-IRS1-Akt signaling axis; microtubule/cytoskeletal regulation via LL5β.

Cellular processes: Impaired cell proliferation, disrupted mitosis/cytokinesis, altered cell migration (cytoskeletal), disrupted chondrocyte proliferation and endochondral ossification.

Protein dysfunction: Loss-of-function of CUL7 (scaffold protein of Golgi-localized E3 ligase), OBSL1 (cytoskeletal adaptor), CCDC8 (coiled-coil complex partner); consequent failure of substrate (IRS-1, cyclin D1, LL5β) ubiquitination/degradation.

Suggested ontology terms: - GO (biological process): GO:0016567 (protein ubiquitination), GO:0043161 (proteasome-mediated ubiquitin-dependent protein catabolic process), GO:0043410 (positive regulation of MAPK cascade)/IGF signaling-related terms, GO:0001501 (skeletal system development), GO:0060350 (endochondral bone morphogenesis) - GO (molecular function): GO:0031625 (ubiquitin protein ligase binding), GO:0004842 (ubiquitin-protein transferase activity) - CL (cell types): CL:0000138 (chondrocyte), CL:0000057 (fibroblast, used in in vitro studies) - UBERON: UBERON:0002102 (growth plate cartilage), UBERON:0001474 (bone element)

7. Anatomical Structures Affected

Organ/system level: - Skeletal system (primary): long bones, vertebral column, pelvis, ribs, hands/feet — UBERON:0001434 (skeletal system) - Craniofacial skeleton and soft tissue: skull shape, facial structure — UBERON:0000033 (head) - Reproductive system (males): testes, scrotum, penile/urethral development (hypospadias) — UBERON:0000473 (testis) - Cardiovascular system: aortic root — UBERON:0002049 (aorta) - Respiratory system: neonatal lung maturation/distress in some populations — UBERON:0002048 (lung) - CNS: spared (normal intelligence)

Tissue/cell level: Growth plate chondrocytes (proliferative zone), cortical/trabecular bone, dermal fibroblasts (used for functional IGF2/H19 studies), Golgi-associated cellular machinery broadly (since CUL7 localizes to the Golgi apparatus).

Subcellular level: Golgi apparatus (site of the 3-M E3 ligase complex) — GO:0005794 (Golgi apparatus); microtubule cytoskeleton — GO:0005874 (microtubule); ubiquitin-proteasome machinery — GO:0000502 (proteasome complex).

Localization/laterality: Findings are generally bilateral and symmetric (proportionate short stature, symmetric limb involvement) — this symmetry is a key differentiator from Silver-Russell syndrome, which classically shows limb-length asymmetry.

8. Temporal Development

Onset: Prenatal — intrauterine growth restriction is evident before birth (low birth weight/length with normal-for-age head circumference), making this a primordial (prenatal-onset) growth disorder rather than a postnatal-onset condition.

Progression: Persistent, non-progressive, lifelong short stature without catch-up growth. The disorder is generally stable rather than degenerative — final adult height is reached without further mechanistic deterioration, though secondary orthopedic (kyphoscoliosis, joint laxity) and endocrine (pubertal, gonadal) complications can evolve over time.

Phenotype evolution with age (per the 2025 natural-history review of 217 cases, PMID 41437277): - Infancy is the period of clearest diagnostic signal — short length/thorax, protuberant abdomen, prominent heels, bulbous/fleshy nasal tip, and the most distinct radiographic long-bone/vertebral findings. - Childhood through adolescence: most dysmorphic and radiographic features progressively attenuate/become "increasingly vague"; short stature and the characteristic nasal appearance persist as the most durable diagnostic clues. - Puberty/adulthood: some males show initially normal pubertal onset followed by secondary (progressive) gonadal failure in adolescence/young adulthood (declining testicular volume, rising gonadotropins) — a later-emerging, evolving feature rather than a static congenital one.

Critical periods: Infancy/early childhood is the critical window for clinical/radiographic diagnosis and for initiating growth hormone trials, given diminishing diagnostic specificity of physical signs with age.

9. Inheritance and Population

Epidemiology: - Prevalence: Not formally established; fewer than ~250 molecularly confirmed cases reported in the literature worldwide since the first description in 1975 (GeneReviews NBK1481); Orphanet lists it as "very rare" with prevalence unknown/<1/1,000,000. - Incidence: Not reported at a population level (too rare for standard surveillance-based incidence estimation).

Inheritance pattern: Autosomal recessive for all three subtypes (3M1/CUL7, 3M2/OBSL1, 3M3/CCDC8). Sibling recurrence risk when both parents are carriers: 25% affected, 50% carrier, 25% unaffected/non-carrier.

Penetrance: Complete (biallelic pathogenic variants are consistently associated with the phenotype).

Expressivity: Variable — facial/skeletal severity and final height vary by gene (CUL7 generally associated with the shortest stature; CCDC8-related disease tends to be milder with relatively higher final height) and to some extent by specific allele (e.g., the Yakut CUL7 founder variant produces a distinct sub-phenotype with high neonatal respiratory distress but comparatively fewer bone abnormalities).

Genetic anticipation: Not applicable/not reported (not a repeat-expansion disorder).

Germline mosaicism: Not specifically documented in the reviewed literature, though standard recessive-disorder recurrence counseling applies.

Founder effects: - Yakut (Sakha) population, Siberia: CUL7 c.4581dupT — described in 43 affected individuals (Maksimova et al. 2007, PMC2652813); associated with high neonatal respiratory distress (~41%) and fewer skeletal anomalies than typical CUL7-related disease. - Maghrebian/Tunisian population: CUL7 c.4451_4452delTG. - Turkish population: OBSL1 c.1273dupA (emerging founder allele).

Consanguinity role: Strongly associated with increased case frequency, as expected for an ultra-rare autosomal recessive disorder; many reported cohorts (e.g., recent Chinese and Middle Eastern case series) note parental consanguinity.

Carrier frequency: Not established at a population level outside founder populations.

Population demographics: Reported cases span diverse ethnic groups (European, Middle Eastern/Maghrebian, East Asian [Chinese, Japanese], Siberian/Yakut, Turkish), consistent with panethnic occurrence with regional founder-variant clustering. No formal sex-ratio skew is reported (autosomal recessive, so no inherent sex bias, aside from male-specific gonadal manifestations being clinically more apparent in males).

10. Diagnostics

Diagnostic criteria (GeneReviews): Diagnosis established in a proband with prenatal-onset persistent growth deficiency plus characteristic clinical and radiographic features, and/or identification of biallelic pathogenic variants in CCDC8, CUL7, or OBSL1 by molecular genetic testing. No formally published consensus clinical scoring criteria exist.

Clinical tests: - Imaging: Skeletal radiographic survey — long bones (slender diaphyses, flared metaphyses), spine (tall vertebral bodies), pelvis (small pelvic bones); echocardiography for aortic root assessment. - Laboratory: IGF-1 levels (monitored during GH trials); gonadotropin/testosterone panel in pubertal/adult males for hypogonadism surveillance. - Prenatal ultrasound: Short long bones and other skeletal findings can be detected as early as 24 weeks' gestation, though findings are not pathognomonic on their own.

Genetic testing: - Recommended approach: multigene panel covering CUL7, OBSL1, CCDC8 (and relevant differential-diagnosis genes), or exome/genome sequencing given phenotypic overlap with other growth-restriction syndromes. - Single-gene sequential testing (starting with CUL7, the most frequently implicated gene) is an alternative in resource-limited settings or when a founder variant is suspected by ancestry. - Prenatal and preimplantation genetic testing are available once familial pathogenic variants are identified (demonstrated in a 2023 Chinese family case, PMC10767403).

Clinical criteria / differential diagnosis (per GeneReviews): - Silver-Russell syndrome: often shows limb-length asymmetry and relative macrocephaly at birth; lacks the classic 3-M long-bone/vertebral radiologic signature; notably, 3-M syndrome shares an IGF2/H19 expression signature with SRS at the molecular level despite distinct genetic causes. - Mulibrey nanism: less severe IUGR; distinct facial gestalt (high forehead, "pseudohydrocephalic" skull). - IGF1R haploinsufficiency/deficiency: microcephaly and intellectual disability common in severe cases (contrasts with normal head size/intelligence in 3-M). - Dubowitz syndrome: microcephaly, eczema, intellectual disability. - Fetal alcohol syndrome: acquired, with microcephaly and nail hypoplasia — important to exclude given overlapping growth restriction/facial features.

Screening: No population-based newborn screening program exists (disorder too rare and non-treatable via early biochemical intervention); diagnosis is clinically/radiographically or genetically triggered rather than screened.

11. Outcome/Prognosis

Survival/mortality: Life expectancy is generally normal. No characteristic disease-specific mortality has been documented outside of population-specific neonatal respiratory distress risk (e.g., Yakut founder variant) and rare complete-knockout-lethal equivalents in constitutive animal models (not applicable to human heterozygous-viable genotypes, since humans with the disease are, by definition, live-born survivors of hypomorphic/partial-loss-of-function alleles).
Morbidity: Primarily orthopedic (kyphoscoliosis, hip dysplasia/dislocation, joint hypermobility-related complications, potential early arthritis), endocrine (progressive gonadal failure in some males), and cardiovascular (aortic root dilatation) morbidity, layered onto lifelong short stature.
Cognitive/functional outcome: Normal intelligence and generally preserved functional independence, distinguishing 3-M syndrome prognostically from many other severe growth-restriction syndromes.
Complications: Neonatal respiratory distress (population-dependent), hip dislocation, scoliosis, joint laxity/early arthritis risk, hypospadias (surgical correction), progressive hypogonadism in some males, aortic root dilation.
Prognostic factors: Causal gene (CUL7 > OBSL1 > CCDC8 in terms of severity/short stature), specific founder variant (e.g., Yakut variant → higher respiratory risk), and timing/response to growth hormone trial.
Recovery potential: Height deficit is not "recovered" — it is a fixed, non-progressive trait once adult stature is reached; management is supportive/adaptive rather than curative.

12. Treatment

Pharmacotherapy — Growth hormone (GH): - Standard of care approach: referral to pediatric endocrinology for a trial of recombinant human growth hormone, particularly in prepubertal children, with close monitoring of growth velocity and IGF-1 levels. - Response is variable: some children show meaningful improvement in growth velocity; others show poor response. A well-documented case (novel CUL7 mutation, associated with neonatal respiratory distress) showed a good response to GH therapy (PMID from PMC4418346, Endocrinol Diabetes Metab Case Rep); another 18-year follow-up case documented 3-M syndrome co-occurring with growth hormone deficiency responding to treatment (PMC3608257, Ital J Pediatr 2013). - One reported individual with CUL7-related disease treated with recombinant human IGF-1 showed a poor response and significant side effects — IGF-1 therapy is not generally favored. - NCIT term: NCIT:C15986 (Pharmacotherapy) as the general treatment_term, with growth hormone as therapeutic_agent (e.g., somatropin, CHEBI-bindable).

Surgical/interventional: - Orthopedic surgery for hip dysplasia/dislocation and progressive kyphoscoliosis (NCIT:C16186, Orthopedic Surgical Procedure). - Surgical limb lengthening is an option for selected patients seeking increased stature (NCIT:C15329, Surgical Procedure). - Urological surgery for hypospadias correction in affected males (NCIT:C15329).

Supportive/rehabilitative: - Physical therapy (NCIT:C15302) and occupational therapy to maximize function and address joint hypermobility/adaptive needs. - Environmental/community adaptations (adaptive equipment, community child-health services) for short stature.

Endocrine management: Monitoring and, where indicated, hormone replacement for males with progressive hypogonadism (testosterone/gonadotropin-guided management by endocrinology).

Surveillance/monitoring protocol (from GeneReviews):

System	Evaluation	Suggested frequency
Growth	Growth chart/velocity	Every 6–12 months
Musculoskeletal	Joint hypermobility, kyphoscoliosis assessment	Annually
Hip	Dislocation screening	Each visit in infancy, especially if walking delayed
Cardiac	Echocardiogram (aortic root)	Consider in adolescence

Experimental/investigational: No gene therapy, RNA-based therapy, or targeted molecular therapy has been developed or trialed for 3-M syndrome; management remains supportive/symptomatic rather than mechanism-targeted, reflecting the structural (ubiquitin-ligase complex assembly) nature of the defect, which is not straightforwardly druggable. No relevant ClinicalTrials.gov interventional trials specific to 3-M syndrome were identified in this search.

Treatment outcomes / adverse events: GH therapy is generally well tolerated in the reported cases with variable efficacy; IGF-1 therapy in the one reported case caused significant side effects with poor efficacy.

13. Prevention

Primary prevention: Not applicable in the traditional sense (no modifiable environmental cause); the only "primary prevention" lever is reproductive/genetic counseling for known carrier couples, particularly in consanguineous unions or founder-variant populations (Yakut, Maghrebian, Turkish).
Secondary prevention (early detection): Prenatal ultrasound surveillance (skeletal findings detectable from ~24 weeks in at-risk pregnancies) and, where familial variants are known, prenatal diagnosis and preimplantation genetic testing (PGT) — demonstrated in a 2023 Chinese family case using novel biallelic CUL7 variants (PMC10767403).
Genetic counseling: Central to prevention/family planning — carrier detection in relatives once the familial variant(s) are known; counseling on the 25% recurrence risk for future pregnancies of carrier couples; sibling evaluation for undiagnosed short stature.
Screening programs: No population-based newborn or carrier screening program exists given extreme rarity, though targeted carrier screening is reasonable in founder populations with known high local carrier frequency.
Tertiary prevention: Surveillance protocol above (orthopedic, cardiac, endocrine) aims to prevent/mitigate secondary complications (scoliosis progression, hip damage, aortic complications, missed hypogonadism) rather than the primary disease process.

14. Other Species / Natural Disease

Naturally occurring veterinary disease: - Sheep (Ovis aries): A recessively inherited disorder in Australian Poll Merino/Merino sheep called Brachygnathia, Cardiomegaly and Renal Hypoplasia Syndrome (BCRHS) was found to be caused by a frameshift variant in OBSL1 (p.(Val573Trpfs119)), representing a naturally occurring ovine model of human 3M syndrome-2. Identification enabled improved breeding management of the affected flock via carrier detection (BMC Genomic Data 2020; OMIA:001595-9940, "Growth disorder, syndromic, OBSL1-related," in Ovis aries*).

Comparative biology / model organisms: - Mouse (Mus musculus), Cul7 knockout: Constitutive Cul7−/− mice are perinatal lethal — severe growth retardation in late gestation and respiratory distress after birth; some models show abnormal bone mineralization, decreased body weight, and reduced bone mineral density; others show severe fetal growth restriction and perinatal death (multiple studies cited in PMC10423707 background). To circumvent lethality, a cartilage-specific conditional knockout (Cul7^fl/fl;Col2a1-CreERT2) was generated: these mice show short/deformed limbs, thickened growth plates, disorganized proliferative-zone chondrocyte columns, and disordered metaphyseal trabecular bone — implicating defective chondrocyte proliferation and endochondral ossification (PMID 38367951, ScienceDirect, "Longitudinal skeletal growth and growth plate morphological characteristics of chondro-tissue specific CUL7 knockout mice"). - Mouse, CCDC8 knockout: A 2023 study (Molecular Biomedicine, PMID 37574524, PMC10423707) established a Ccdc8−/− mouse model; knockout was highly lethal (only 4 live-born knockouts from 410 mice bred, <1% success rate), with placental developmental disorder, intrauterine growth retardation, intrauterine death, and perinatal death closely paralleling Cul7 knockout embryo phenotypes — supporting the shared-pathway model of CUL7/OBSL1/CCDC8 function. - OBSL1 knockout studies (Hanson et al. 2009, PMC2694976) established the direct physical and functional link between OBSL1 and the CUL7-containing E3 ligase complex, foundational to the current mechanistic model.

Cross-species relevance: These animal models (sheep OBSL1, mouse Cul7/Ccdc8) confirm cross-species conservation of the 3-M E3 complex's essential role in fetal/perinatal growth and support their use for mechanistic and (potentially) therapeutic research, though the severe perinatal lethality of constitutive knockouts limits their use to conditional/tissue-specific systems for postnatal phenotyping.

Zoonotic potential: None — this is a purely genetic (non-infectious) disorder; no transmission risk.

15. Model Organisms

Model	Type	Key features	Reference
Cul7−/− mouse (constitutive)	Genetic knockout, mammalian	Perinatal lethal; late-gestation growth retardation, respiratory distress at birth; some lines show abnormal bone mineralization and reduced BMD	Cited in PMC10423707 background
Cul7^fl/fl;Col2a1-CreERT2 mouse	Conditional/tissue-specific (cartilage) knockout	Short/deformed limbs, thickened growth plate, disorganized proliferative chondrocytes, disordered metaphyseal trabecular bone; viable, enabling postnatal skeletal phenotyping	PMID 38367951
Ccdc8−/− mouse	Constitutive knockout	Highly lethal (<1% live-birth rate of homozygotes); placental defects, IUGR, intrauterine/perinatal death mirroring Cul7 knockouts	PMID 37574524 / PMC10423707
Merino/Poll Merino sheep, OBSL1 frameshift	Naturally occurring animal model	BCRHS: brachygnathia, cardiomegaly, renal hypoplasia; ovine model of human 3M syndrome-2; enabled breeding-based carrier management	BMC Genomic Data 2020 / OMIA:001595-9940
Human dermal fibroblasts (patient-derived)	Cellular/in vitro	Reduced IGF2 expression, increased H19 expression, reduced IGF-II secretion vs. controls; used to demonstrate the IGF2-silencing mechanism	PMID 24148222

Applications: These models collectively support study of (a) the shared CUL7-OBSL1-CCDC8 E3-ligase-complex biology, (b) chondrocyte/growth-plate-specific consequences of complex loss, (c) placental/perinatal growth-restriction mechanisms, and (d) potential future therapeutic-target validation (e.g., IGF-1/Akt pathway modulation), though no model has yet been used for interventional (drug) testing specific to 3-M syndrome in the literature surveyed.

Model limitations: Constitutive knockouts in mouse (Cul7, Ccdc8) are embryonic/perinatal lethal and thus do not recapitulate the live-born, postnatal phenotype seen in humans (who carry hypomorphic/partial-loss-of-function alleles rather than complete null states compatible only with lethality) — a clear human-model mismatch: conditional/tissue-specific knockouts were required to generate a viable, phenotypically informative postnatal model. The sheep OBSL1 model, by contrast, is a naturally occurring, viable (in appropriate genotype/zygosity) large-animal model that may better approximate the human postnatal skeletal phenotype, though comparative fidelity has not been formally characterized against the human 3-M radiographic signature.

Summary Table: Suggested Ontology Bindings

Category	Term
Disease	MONDO:0007477 (3M syndrome 1); OMIM #273750/#612921/#614205; ORPHA:2616
Genes	hgnc CUL7, hgnc OBSL1, hgnc CCDC8 (verify current HGNC IDs before curation)
Phenotypes (HP)	HP:0004322 Short stature; HP:0001511 IUGR; HP:0002938 Hyperlordosis; HP:0001382 Joint hypermobility; HP:0002751 Kyphoscoliosis; HP:0000047 Hypospadias; HP:0000268 Dolichocephaly; HP:0011800 Midface retrusion
GO (BP)	GO:0016567 protein ubiquitination; GO:0060350 endochondral bone morphogenesis
GO (CC)	GO:0005794 Golgi apparatus
CL	CL:0000138 chondrocyte
UBERON	UBERON:0002102 growth plate cartilage
NCIT (treatment)	NCIT:C15986 Pharmacotherapy (GH); NCIT:C16186 Orthopedic Surgical Procedure; NCIT:C15302 Physical Therapy

Sources

3-M Syndrome – GeneReviews (NBK1481)
OMIM #273750 – THREE M SYNDROME 1
OMIM #612921 – THREE M SYNDROME 2
OMIM #614205 – THREE M SYNDROME 3
Orphanet: 3M syndrome (ORPHA2616)
NORD: Three M Syndrome
Hanson D et al., "The Primordial Growth Disorder 3-M Syndrome Connects Ubiquitination to the Cytoskeletal Adaptor OBSL1," Am J Hum Genet 2009, PMID 19481195 — PMC2694976
Meyer R et al., "3-M syndrome: a growth disorder associated with IGF2 silencing," Endocr Connect 2013, PMID 24148222 — PMC3847915
Maksimova N et al., "Clinical, molecular and histopathological features of short stature syndrome with novel CUL7 mutation in Yakuts," 2007 — PMC2652813
"3-M syndrome: evolution of the phenotype over time," Ital J Pediatr, Dec 2025, PMID 41437277, DOI 10.1186/s13052-025-02172-8 — PMC12838503
"Establishment of the 3M syndrome animal model in CCDC8 knockout mice," Mol Biomed 2023, PMID 37574524 — PMC10423707
"Longitudinal skeletal growth and growth plate morphological characteristics of chondro-tissue specific CUL7 knockout mice," PMID 38367951 — ScienceDirect
"Molecular basis of a new ovine model for human 3M syndrome-2," BMC Genomic Data 2020 — Springer; PMC7493961
Aldhoon-Hainerová I et al., "Gonadal Failure in a Male With 3-M Syndrome," JCEM Case Rep 2024, PMID 38847008 — PMC11154130
"Chinese patients with 3M syndrome: clinical manifestations and two novel pathogenic variants," Front Genet 2023 — Frontiers
"3-M syndrome: a novel CUL7 mutation associated with respiratory distress and a good response to GH therapy" — PMC4418346
"3-M syndrome associated with growth hormone deficiency: 18 year follow-up of a patient," Ital J Pediatr 2013 — PMC3608257
"Prenatal diagnosis and preimplantation genetics testing of 3M syndrome in a Chinese family with novel biallelic variants of CUL7" — PMC10767403
Society for Endocrinology, "Loss of the Golgi localised E3 ubiquitin ligase containing Cullin 7 in 3-M syndrome leads to reduced cell proliferation and reduced IGF1 mediated activation of Akt" — Endocrine Abstracts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	19
Resolved	19
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	2
Quoted claims found in source	2
Quoted claims not found in source	0
References weighed for topical relevance	19
On topic	13
Off topic	0

All extracted references resolved successfully.

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Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

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Diagnosis

Prevalence

Experimental Models

Animal Models

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References & Deep Research

References

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3-M Syndrome: Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

Growth phenotype

Craniofacial features

Musculoskeletal features

Radiographic (skeletal) hallmark features

Neurodevelopmental

Endocrine/reproductive

Cardiac

Respiratory

Quality of life

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary Table: Suggested Ontology Bindings

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