Gillessen-Kaesbach-Nishimura Syndrome

A number sign (#) is used with this entry because of evidence that Gillessen-Kaesbach-Nishimura syndrome (GIKANIS) is caused by homozygous mutation in the ALG9 gene (606941) on chromosome 11q23.

Homozygous mutation in the ALG9 gene can also cause congenital disorder of glycosylation type Il (CDG1L; 608776).

Description

Gillessen-Kaesbach-Nishimura syndrome is an autosomal recessive multiple congenital anomaly disorder characterized by skeletal dysplasia, dysmorphic facial features, and variable visceral abnormalities, including polycystic kidneys, diaphragmatic hernia, lung hypoplasia, and congenital heart defects. It may be lethal in utero or early in life. The disorder is at the severe end of the phenotypic spectrum of congenital disorders of glycosylation (summary by Tham et al., 2016).

Clinical Features

Gillessen-Kaesbach et al. (1993) reported the cases of 3 pairs of sibs from unrelated families who presented with polycystic kidneys of the type thought to be specific for autosomal recessive polycystic kidney disease (see ARPKD, 263200) and with microbrachycephaly, hypertelorism with telecanthus, large posteriorly angulated and fleshy ears, and various congenital malformations including congenital heart defects. Two of the families were Turkish with consanguineous parents.

Nishimura et al. (1998) reported 2 Japanese sibs, children of consanguineous parents, with a lethal mesomelic osteochondrodysplasia. They were born at 34 and 35 weeks' gestation, respectively. The older sib died during labor and the younger at 1 week of age. The older sib had facial dysmorphism, including abundant hair, sloping forehead, aniridia, long palpebral fissures, prominent nasal bridge with beaked nose, flat philtrum with upturned upper lip, micrognathia with cleft palate, and low-set fleshy ears. There were multiple joint contractures and mesomelic shortening of the limbs, but the fingers and toes were not stubby. Radiographs showed mesomelic shortening of the forearms with bowed and thickened radii and ulnae, lack or partial ossification of the cervical vertebral bodies, round ilia, delayed ossification of the pubic bones, and thick, sclerotic occiput. Autopsy showed diaphragmatic hernia, abnormal lung lobulation, periportal hepatic fibrosis, cystic dilation of the bile ducts, and mild ductal dilation of the pancreas. There was a multilocular cyst in the right kidney, but no cystic dysplasia. Other features included microcephaly with ectopic gray matter and focal laminar necrosis and migration abnormalities in the cerebellum. The younger sib had similar features, although autopsy was not performed. Both also had thrombocytopenia. Nishimura et al. (1998) noted the phenotypic similarities to the patients reported by Gillessen-Kaesbach et al. (1993).

Hallermann et al. (2000) reported 2 male sibs with a syndrome similar to that described by Gillessen-Kaesbach et al. (1993). The patients had polycystic kidneys and hepatic fibrosis typical of that observed in autosomal recessive polycystic kidney disease, along with skeletal and facial anomalies. Skeletal abnormalities included 'butterfly' vertebrae, distinctive shape of the iliac bones, and brachymelia. The facial anomalies included hypertelorism, epicanthic folds, and anteverted nares.

Tham et al. (2016) reported a stillborn girl, born of consanguineous Turkish parents, and 2 fetuses, conceived of consanguineous Iraqi parents, with a lethal multiple congenital malformation disorder detected in utero. The first fetus had a ventricular septal defect, double outlet right ventricle with anomalous outflow tract, and enlarged hyperechogenic polycystic kidneys associated with oligohydramnios. Prenatal ultrasound of the fetuses in the second family showed echogenic kidneys with hydronephrosis and brachymelia. All 3 patients had overlapping dysmorphic features, including hypertelorism, beaked nose, hypoplastic alae nasi, microretrognathia, low-set and posteriorly rotated ears, short neck, and short extremities with ulnar deviation of the hands and deformed feet. Other features included lung hypoplasia with abnormal lung lobulation. Radiographic studies showed decreased ossification of the frontoparietal bones, thickening of the occipital bones, deficient ossification of the cervical vertebral bodies and pubic bones, round pelvis, and short tubular bones with metaphyseal flaring. Analysis of spleen tissue showed underglycosylation of transferrin (190000), consistent with a congenital disorder of glycosylation.

Inheritance

The transmission pattern of Gillessen-Kaesbach-Nishimura syndrome in the families reported by Tham et al. (2016) was consistent with autosomal recessive inheritance.

Mapping

By homozygosity mapping in 2 unrelated families segregating Gillessen-Kaesbach-Nishimura syndrome, Tham et al. (2016) identified a common haplotype in affected members of both families. Combined analysis of the polymorphic markers and SNPs from whole-exome sequencing indicated that the shared homozygous region encompassed 1.75-2.18 Mb, including the ALG9 gene, on chromosome 11.

Exclusion Studies

Hallermann et al. (2000) performed linkage analysis using markers from the 6p21.1-p12 region (to which a form of ARPKD (see 263200) had been mapped) in the sibs they reported with ARPKD and associated features. The sibs had different haplotypes, thus excluding the locus on chromosome 6p.

Molecular Genetics

In a stillborn girl and 2 fetuses from 2 unrelated consanguineous families with GIKANIS, Tham et al. (2016) identified a homozygous truncating mutation in the ALG9 gene (606941.0003). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Haplotype analysis suggested a founder effect. The 2 fetuses from the second family were also homozygous for a rare missense variant (D968H) affecting a highly conserved residue in the ANK3 gene (600465); mutation in the ANK3 gene is associated with autosomal recessive mental retardation-37 (MRT37; 615493). The parents were heterozygous carriers of the ANK3 variant.