A disorder characterized by short stature of variable severity with postnatal onset. The most constant radiographic abnormalities are observed in the tubular bones of the hands and in the proximal part of the femur. Cone-shaped epiphyses or a similar epiphyseal configuration with premature epimetaphyseal fusion result in shortening of the skeletal components involved. Cone-shaped epiphyses are also present to a variable extent at the shoulders, knees and ankles.

Phenotype	Protein			Mutations ( Buried, Surf., Int., Not Classified)
Acrocapitofemoral dysplasia	IHH	Indian hedgehog protein	Q14623	V190A Buried mutation SwissVar: VAR_015986  P46L Surface mutation SwissVar: VAR_015981

An autosomal recessive acromesomelic chondrodysplasia. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbsand hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). AMDG is characterized by normal axial skeletons and missing or fused skeletal elements within the hands and feet.

Phenotype	Protein			Mutations ( Buried, Surf., Int., Not Classified)
Acromesomelic chondrodysplasia, Grebe type	GDF5	Growth/differentiation factor 5	P43026	C400Y Buried mutation SwissVar: VAR_017407

Severe skeletal dysplasia.

Phenotype	Protein			Mutations ( Buried, Surf., Int., Not Classified)
Chondrodysplasia Blomstrand type	PTH1R	Parathyroid hormone/parathyroid hormone-related peptide receptor	Q03431	P132L Surface mutation SwissVar: VAR_016062

Autosomal dominant cancer predisposition syndrome associated with elevated risk for tumors of the breast, thyroid and skin. The predominant phenotype for CD is multiple hamartoma syndrome, in many organ systems including the breast (70% of CD patients), thyroid (40- 60%), skin, CNS (40%), gastrointestinal tract. Affected individuals are at an increased risk of both breast and thyroid cancers. Trichilemmomas (benign tumors of the hair follicle infundibulum), and mucocutaneous papillomatosis (99%) are hallmarks of CD.

Phenotype	Protein			Mutations ( Buried, Surf., Int., Not Classified)
Cowden disease	BMPR1A	Bone morphogenetic protein receptor type-1A	P36894	A338D Buried mutation SwissVar: VAR_015534

Rare autosomal recessive condition characterized by absence of the fibulae and severe acromesomelic limb shortening with small, non- functional toes. Although milder, the phenotype resembles the autosomal recessive Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia.

Phenotype	Protein			Mutations ( Buried, Surf., Int., Not Classified)
Du Pan syndrome	GDF5	Growth/differentiation factor 5	P43026	L441P Buried mutation SwissVar: VAR_017408  Also present in: Brachydactyly A2 P436T Interface mutation SwissVar: VAR_054911  Interactions affected: BMPR1A GDF5 BMPR1B GDF5 S439T Interface mutation SwissVar: VAR_037980  Interactions affected: BMPR1A GDF5 BMPR1B GDF5 H440L Interface mutation SwissVar: VAR_037981  Interactions affected: BMPR1A GDF5 BMPR1B GDF5 R378Q Cannot be mapped on a structure. SwissVar: VAR_054910

A condition characterized by multiple formation of enchondromas, benign neoplasms derived from mesodermal cells that form cartilage. Enchondromas remain within the substance of a cartilage or bone. Clinical problems caused by enchondromas include skeletal deformity and the potential for malignant change to osteosarcoma.

Phenotype	Protein			Mutations ( Buried, Surf., Int., Not Classified)
Enchondromatosis multiple	PTH1R	Parathyroid hormone/parathyroid hormone-related peptide receptor	Q03431	R150C Interface mutation SwissVar: VAR_016063  Interactions affected: PTH1R PTH1R

A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability.

Phenotype	Protein			Mutations ( Buried, Surf., Int., NC)
Holoprosencephaly 11	CDON	Cell adhesion molecule-related/down-regulated by oncogenes	Q4KMG0	T684S Cannot be mapped on a structure. SwissVar: VAR_066497  P689A Cannot be mapped on a structure. SwissVar: VAR_066498  V691M Cannot be mapped on a structure. SwissVar: VAR_066499  V780E Cannot be mapped on a structure. SwissVar: VAR_066500  T790A Cannot be mapped on a structure. SwissVar: VAR_066501  S940R Cannot be mapped on a structure. SwissVar: VAR_066502

JP/HHT syndrome phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT) [MIM:187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or ACVRL1. All four genes encode proteins involved in the transforming-growth-factor-signaling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic etiology of this association is unknown.

Phenotype	Protein			Mutations ( Buried, Surf., Int., NC)
Juvenile polyposis syndrome	BMPR1A	Bone morphogenetic protein receptor type-1A	P36894	C82Y Buried mutation SwissVar: VAR_022829  C376Y Buried mutation SwissVar: VAR_015535  M470T Buried mutation SwissVar: VAR_022832  C124R Surface mutation SwissVar: VAR_015533  R443C Surface mutation SwissVar: VAR_022831  Y62D Interface mutation SwissVar: VAR_022828  Interactions affected: BMPR1A BMPR1A C130R Interface mutation SwissVar: VAR_022830  Interactions affected: BMPR1A BMPR1A

Rare autosomal dominant disorder characterized by a short-limbed dwarfism associated with hypercalcemia and normal or low serum concentrations of the two parathyroid hormones.

Phenotype	Protein			Mutations ( Buried, Surf., Int., NC)
Jansen metaphyseal chondrodysplasia	PTH1R	Parathyroid hormone/parathyroid hormone-related peptide receptor	Q03431	H223R Cannot be mapped on a structure. SwissVar: VAR_003582  T410P Cannot be mapped on a structure. SwissVar: VAR_003583  T410R Cannot be mapped on a structure. SwissVar: VAR_038811  I458R Cannot be mapped on a structure. SwissVar: VAR_016064

A bone disease characterized by multiple progressive joint fusions that commonly involve proximal interphalangeal, tarsal-carpal, humeroradial and cervical spine joints. Additional features can include progressive conductive deafness and facial dysmorphism.

Phenotype	Protein			Mutations ( Buried, Surf., Int., NC)
Multiple synostoses syndrome 1	NOG	Noggin	Q13253	W217G Surface mutation SwissVar: VAR_011363  C232W Surface mutation SwissVar: VAR_064541
Multiple synostoses syndrome 2	GDF5	Growth/differentiation factor 5	P43026	R438L Interface mutation SwissVar: VAR_026545  Also present in: Symphalangism proximal syndrome Interactions affected: BMPR1A GDF5 BMPR1B GDF5 S475N Interface mutation SwissVar: VAR_037982  Interactions affected: GDF5 BMPR2

A rare disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial PPH1 is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs.

Phenotype	Protein			Mutations ( Buried, Surf., Int., NC)
Primary pulmonary hypertension	BMPR2	Bone morphogenetic protein receptor type-2	Q13873	C60Y Buried mutation SwissVar: VAR_013670  C118W Buried mutation SwissVar: VAR_013672  C347Y Buried mutation SwissVar: VAR_013676  C420R Buried mutation SwissVar: VAR_013677  C483R Buried mutation SwissVar: VAR_013678  Q82H Surface mutation SwissVar: VAR_033109  C117Y Surface mutation SwissVar: VAR_013671  C123R Surface mutation SwissVar: VAR_013673  C123S Surface mutation SwissVar: VAR_013674  D485G Surface mutation SwissVar: VAR_013679  R491Q Surface mutation SwissVar: VAR_013680  R491W Surface mutation SwissVar: VAR_013681  G182D Cannot be mapped on a structure. SwissVar: VAR_033110  K512T Cannot be mapped on a structure. SwissVar: VAR_013682  N519K Cannot be mapped on a structure. SwissVar: VAR_013683  R899P Cannot be mapped on a structure. SwissVar: VAR_033111

Characterized by the hereditary absence of the proximal interphalangeal (PIP) joints (Cushing symphalangism). Severity of PIP joint involvement diminishes towards the radial side. Distal interphalangeal joints are less frequently involved and metacarpophalangeal joints are rarely affected whereas carpal bone malformation and fusion are common. In the lower extremities, tarsal bone coalition is common. Conducive hearing loss is seen and is due to fusion of the stapes to the petrous part of the temporal bone.

Phenotype	Protein			Mutations ( Buried, Surf., Int., NC)
Symphalangism proximal syndrome	GDF5	Growth/differentiation factor 5	P43026	R438L Interface mutation SwissVar: VAR_026545  Also present in: Multiple synostoses syndrome 2 Interactions affected: BMPR1A GDF5 BMPR1B GDF5 E491K Interface mutation SwissVar: VAR_037983  Interactions affected: BMPR1A GDF5 BMPR1B GDF5 GDF5 GDF5 L373R Cannot be mapped on a structure. SwissVar: VAR_054909
	NOG	Noggin	Q13253	C184Y Buried mutation SwissVar: VAR_018325  G189C Surface mutation SwissVar: VAR_011362  W205C Surface mutation SwissVar: VAR_037605  P35R Interface mutation SwissVar: VAR_011361  Also present in: Tarsal-carpal coalition syndrome Interactions affected: BMP2 NOG BMP7 NOG P35S Interface mutation SwissVar: VAR_018324  Also present in: Brachydactyly B2 Interactions affected: BMP2 NOG BMP7 NOG I220N Interface mutation SwissVar: VAR_011364  Interactions affected: BMP2 NOG BMP7 NOG Y222C Interface mutation SwissVar: VAR_011365  Also present in: Tarsal-carpal coalition syndrome Interactions affected: BMP2 NOG BMP7 NOG Y222D Interface mutation SwissVar: VAR_011366  Interactions affected: BMP2 NOG BMP7 NOG P223L Interface mutation SwissVar: VAR_011367  Interactions affected: BMP2 NOG BMP7 NOG

Syndactyly is an autosomal dominant trait and is the most common congenital anomaly of the hand or foot. It is marked by persistence of the webbing between adjacent digits, so they are more or less completely attached. In this type there is usually complete and bilateral syndactyly between the fourth and fifth fingers. Usually it is soft tissue syndactyly but occasionally the distal phalanges are fused. The fifth finger is short with absent or rudimentary middle phalanx. The feet are not affected.

Phenotype	Protein			Mutations ( Buried, Surf., Int., NC)
Syndactyly 5	HOXD13	Homeobox protein Hox-D13	P35453	Q325R Surface mutation SwissVar: VAR_031652

Limb malformation that shows a characteristic manifestation in both hands and feet. This condition is inherited as an autosomal dominant trait with reduced penetrance.

Phenotype	Protein			Mutations ( Buried, Surf., Int., NC)
Synpolydactyly 1	HOXD13	Homeobox protein Hox-D13	P35453	R306W Surface mutation SwissVar: VAR_031651

Autosomal dominant disorder characterized by fusion of the carpals, tarsals and phalanges, short first metacarpals causing brachydactyly, and humeroradial fusion. TCC is allelic to SYM1, and different mutations in NOG can result in either TCC or SYM1 in different families.

Phenotype	Protein			Mutations ( Buried, Surf., Int., NC)
Tarsal-carpal coalition syndrome	NOG	Noggin	Q13253	P35R Interface mutation SwissVar: VAR_011361  Also present in: Symphalangism proximal syndrome Interactions affected: BMP2 NOG BMP7 NOG R204L Interface mutation SwissVar: VAR_018326  Interactions affected: BMP2 NOG BMP7 NOG Y222C Interface mutation SwissVar: VAR_011365  Also present in: Symphalangism proximal syndrome Interactions affected: BMP2 NOG BMP7 NOG