Endocrine-Cerebroosteodysplasia

A number sign (#) is used with this entry because of evidence that endocrine-cerebroosteodysplasia (ECO) is caused by homozygous mutation in the ICK gene (612325), encoding intestinal cell kinase, on chromosome 6p12.

Clinical Features

Lahiry et al. (2009) reported 6 affected infants from 2 families in the Old Order Amish community with a syndrome comprising endocrine, cerebral, and skeletal abnormalities. One infant died on day 3 of life, another during birth, and the other pregnancies were therapeutically terminated between 23 and 29 weeks' gestation due to severe malformations identified on prenatal ultrasound. Clinical features included hydrocephalus with ventriculomegaly, facial dysmorphism, including wide nasal bridge, cleft lip/palate, small sunken eyes, eyelid fusion, and dysplastic ears. The upper limbs were markedly shortened with bowing of the forearms, ulnar deviation of the hands, postaxial polydactyly, brachydactyly, and syndactyly. Lower limb anomalies included abducted hips and abnormal toes. Four 46,XY males had varying degrees of abnormal differentiation of the external genitalia, and some patients had cystically dilated renal tubules. Neuropathologic findings were extensive and included evidence of holoprosencephaly, hypoplastic or absent corpus callosum, and cerebral cortex malformations. In addition, affected individuals had hypoplastic adrenal and pituitary glands. Lahiry et al. (2009) noted that many of the malformations observed suggested a defect of apoptosis, especially the cleft lip and palate, syndactyly, prolonged persistence of fusion of the eyelids, and unfused urogenital folds. The authors also noted some phenotypic similarities to Majewski syndrome (263520) and hydrolethalus syndrome (236680).

Oud et al. (2016) studied a 33-week-gestation Turkish fetus initially diagnosed with short-rib thoracic dysplasia (SRTD; see 208500). In addition to hydropic appearance, short thorax, and very short limbs, postmortem examination revealed orofaciodigital defects including high and broad forehead, deep-set eyes, hypertelorism, small nose, anteverted nares, midline pseudocleft of the upper lip, cleft soft palate, natal teeth, labiogingival fusion, irregular alveolar crest, fusion of tongue to lower palate, multiple frenula, micrognathia, low-set and posteriorly rotated ears, postaxial heptadactyly of the hands, and preaxial heptadactyly of the feet. Sex reversal with hypoplastic labial folds and anterior ectopic anus were also noted. Radiographs showed resemblance to SRTD type II, with very short tubular bones, torpedo-like femora, ovoid hypoplastic tibiae, premature epiphyseal ossifications in the lower limbs, short ribs, mildly defective ossification of the vertebrae, and small ilia with normal shape. After discovery of a homozygous mutation in the ICK gene (see MOLECULAR GENETICS), the authors noted significant clinical overlap with the previously reported Amish patients, and concluded that they had identified the second family with ECO syndrome worldwide.

Inheritance

The disorder in the family reported by Lahiry et al. (2009) followed an autosomal recessive pattern of inheritance.

Mapping

By genomewide linkage analysis of Amish families with ECO, Lahiry et al. (2009) found linkage to chromosome 6p12.2-p12.

Molecular Genetics

In affected members of Old Order Amish families with ECO, Lahiry et al. (2009) identified a homozygous mutation in the ICK gene (612325.0001).

By whole-exome sequencing in a Turkish fetus with ciliopathy-related features, Oud et al. (2016) identified homozygosity for a missense mutation in the ICK gene (G120C; 612325.0006) that segregated fully with disease in the family and was not found in Turkish controls or public variant databases.