Keppen-Lubinsky Syndrome

A number sign (#) is used with this entry because of evidence that Keppen-Lubinsky syndrome (KPLBS) is caused by heterozygous mutation in the KCNJ6 gene (600877) on chromosome 21q22.

Description

Keppen-Lubinsky syndrome is a very rare disorder characterized by severely delayed psychomotor development, hypertonia, hyperreflexia, generalized lipodystrophy giving an aged appearance, and distinctive dysmorphic features, including microcephaly, prominent eyes, narrow nasal bridge, and open mouth (summary by Masotti et al., 2015).

Clinical Features

Gorlin et al. (2001) referred to a 5-year-old boy examined by Keppen and Lubinsky who had severe developmental delay and a distinct facial appearance with tightly adherent skin reminiscent of severe lipodystrophy. All growth parameters were low; brain MRI was normal. Beare-Stevenson cutis gyrata syndrome (BSTVS; 123790) was excluded.

De Brasi et al. (2003) reported an 8-year-old boy with generalized lipodystrophy, peculiar aged facial appearance with tight, thin skin overlying the facial bones and small pinched nose, and almost complete lack of psychomotor development. They noted the similarities to the patient reported by Gorlin et al. (2001), and suggested that this is a novel progeroid syndrome characterized by normal growth parameters at birth, very poor postnatal growth, failure to thrive, and developmental delay.

Basel-Vanagaite et al. (2009) reported a third boy with features consistent with Keppen-Lubinsky syndrome. He was born of unrelated Jewish parents of Yemenite origin and had a normal birth weight. He showed severe developmental delay with behavioral anomalies, including self-mutilation and chewing of the tongue and lips. He also had episodes of opisthotonic posturing and febrile seizures. Physical examination at age 6 years, 9 months showed poor growth and decreased facial subcutaneous fat with tightly adherent facial skin, large prominent eyes, pinched nose with hypoplastic alae, short philtrum, tented upper lip, open mouth, and high-arched palate. Subcutaneous fat on the rest of the body was normal. He was very jittery and responded to minimal external stimulation with body arching. Hypertonia and hyperreflexia were also present. Laboratory investigations showed no abnormalities.

Masotti et al. (2015) reported a boy with KPLBS. He had a striking appearance, with wrinkled forehead and chin skin and tightly adherent facial skin due to absence of subcutaneous tissue. Additional features included prominent eyes, protruding nasal tip, narrow and high-arched palate, and micrognathia. He also had hypertonia, flexion contractures, and scoliosis. Onset of seizures occurred in infancy. He was severely disabled and underwent a tracheostomy for respiratory insufficiency.

Molecular Genetics

In the patients with KPLBS reported by De Brasi et al. (2003) and Basel-Vanagaite et al. (2009), Masotti et al. (2015) identified 2 different de novo heterozygous mutations in the KCNJ6 gene (c.455_457del, 600877.0001 and G154S, 600877.0002, respectively). A third patient with the disorder was found to carry the same c.455_457del mutation, also heterozygous and de novo, identified in the patient reported by De Brasi et al. (2003). The mutations were found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants were not performed, but 3D structural modeling suggested that the mutations would alter channel function. Masotti et al. (2015) noted that the mouse 'weaver' mutant is caused by a G156S substitution in the Kcnj6 gene, which corresponds to the G154S mutation. These mutant mice have neuronal death attributable to the loss of Kcnj6 currents, resulting in excessive neuronal depolarization, excitability, and seizures.

Animal Model

The weaver mutation, discovered by Lane (1964), had been studied intensively for more than 25 years (Rakic and Sidman, 1973) for insights into the normal processes of neural development and differentiation. Homozygous animals suffer from severe ataxia that is obvious by about the second postnatal week. The cerebellum of these animals is drastically reduced in size due to depletion of the granule cell neuron, the major cell type of cerebellum. Heterozygous animals are not ataxic but have an intermediate number of surviving granule cells. Patil et al. (1995) and others before them found that the overall expression pattern of the Girk2 gene (Kcnj6) corresponds closely to the pattern of phenotypic effects in weaver mice. Expression in the cerebellum, substantia nigra, and testes is associated with a developmental loss of cells in those tissues. Expression of Girk2 in the cortex is consistent with seizures that affect weaver mice. Patil et al. (1995) reported a missense mutation in the Girk2 gene in the weaver mouse: a G-to-A transition at position 953 replaced a gly with ser at residue 156 in the Girk2 protein.