Acromesomelic Dysplasia, Demirhan Type

A number sign (#) is used with this entry because of evidence that the Demirhan type of acromesomelic dysplasia (AMDD) is caused by homozygous mutation in the BMPR1B gene (603248) on chromosome 4q22.

Clinical Features

Demirhan et al. (2005) reported a 16-year-old girl from a multiconsanguineous family who had a severe limb malformation consisting of severe brachydactyly with radial deviation of the fingers, ulnar deviation of the hands, fusion of the carpal/tarsal bones, aplasia of the fibula, and bilateral clubfoot deformity with small broad feet and short toes that appeared constricted at their bases. In addition, she had genital anomalies and primary amenorrhea; ultrasound examination revealed absence of the ovaries and hypoplasia of the uterus, and endocrinologic studies confirmed hypergonadotropic hypogonadism.

Graul-Neumann et al. (2014) described 2 consanguineous families in which 3 individuals (1 female and 2 males) had a severe form of limb malformation consisting of bilateral aplasia of the fibula, severe brachydactyly, and carpal/tarsal fusion. One affected individual also had bowing of tibiae and radii. The mother in the first family had mild type A2 brachydactyly (BDA2; 112600) with shortened middle phalanges of the second and fifth fingers and toes. Both parents in the second family were short of stature; the father also had mild generalized brachydactyly. Graul-Neumann et al. (2014) diagnosed the patients with Grebe-type acromesomelic dysplasia (AMDG; 200700).

Stange et al. (2015) described an individual with disproportionate short stature, mild acromesomelic dysplasia, limb shortening, absent fibulae, short fingers, abnormal finger joints with deviations, and hypoplastic toes with broad and short toenails. Abdominal ultrasound was normal, with the presence of a uterus and ovaries of normal size and shape. There was no hypergonadotropic hypogonadism, and the patient had normal levels of luteinizing hormone, follicle-stimulating hormone, estradiol, and progesterone. Stange et al. (2015) diagnosed the patient with du Pan acromesomelic dysplasia (228900).

Molecular Genetics

In a 16-year-old girl from a multiconsanguineous family who had acromesomelic chondrodysplasia and genital anomalies, Demirhan et al. (2005) identified homozygosity for an 8-bp deletion in the BMPR1B gene (603248.0003). Both parents and 2 sibs were heterozygous for the deletion.

In 3 individuals from 2 consanguineous families with acromesomelic dysplasia without genital anomalies, Graul-Neumann et al. (2014) excluded mutation in the GDF5 gene (601146) and identified a homozygous missense (C53R; 603248.0005) or nonsense (W219X; 603248.0006) mutation in the BMPR1B gene. The mutations were detected in heterozygous state in both sets of parents. Graul-Neumann et al. (2014) diagnosed the patients with Grebe-type acromesomelic dysplasia.

In a 38-year-old woman, born of first-cousin parents originating from Morocco, with acromesomelic dysplasia without genital anomalies, Stange et al. (2015) excluded mutation in the GDF5 gene and identified homozygosity for an R31C mutation (603248.0007) in the BMPR1B gene. The patient was 1 of 11 sibs; 1 sister and 2 brothers were reportedly affected, but they were not available for study. No DNA from other affected or unaffected family members was available for segregation analysis. Stange et al. (2015) diagnosed the patient with du Pan acromesomelic dysplasia.