A patient with Keipert syndrome and isolated fibrous dysplasia of the sphenoid sinus

Derbent, Murat; Bikmaz, Yunus Emre; Ağıldere, Muhteşem

doi:10.1002/ajmg.a.34006

Cited by 4 publications

(3 citation statements)

References 6 publications

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“…Keipert syndrome, also known as nasodigitoacoustic syndrome (MIM: 255980), is a rare, X-linked disorder characterized by craniofacial and digital abnormalities and variable learning difficulties and sensorineural deafness. 1 Keipert et al 2 first described the syndrome in two brothers, and it has subsequently been reported in one other male sibling pair, 3 five isolated male individuals, [4][5][6][7] and a girl and her less severely affected father. 8 The facial appearance is distinctive and comprises a broad forehead, hypertelorism, a prominent nose, a wide mouth, and a prominent upper lip with a cupid's bow configuration.…”

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confidence: 99%

Pathogenic Variants in GPC4 Cause Keipert Syndrome

Amor

Stephenson

Mustapha

et al. 2019

The American Journal of Human Genetics

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Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506* and p.Glu496* were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

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confidence: 99%

Pathogenic Variants in GPC4 Cause Keipert Syndrome

Amor

Stephenson

Mustapha

et al. 2019

The American Journal of Human Genetics

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“…kazuistyka / case report oraz zespół Mc-Cune'a-Albrighta [5]. Postać monosteotyczna dotyczy jednej kości i najczęściej lokalizuje się w żebrach lub kościach twarzoczaszki.…”

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“…w przypadkach poliosteotycznego wariantu choroby [4]. Zajęcie zatoki klinowej powoduje bóle głowy, zaburzenia widzenia, podwójne widzenie, zatkanie nosa i opadnięcie powieki [5,9]. W diagnostyce kluczową rolę odgrywa badanie rezonansu magnetycznego i tomografii komputerowej.…”

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Fibrous dysplasia of sphenoid bone – diagnostic difficulties

Wardas¹,

Piotrowska-Seweryn²,

Markowski³

et al. 2015

Polski Przegląd Otorynolaryngologiczny

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GPC4 truncating variant associated with Keipert syndrome and lacrimal punctal agenesis

Kuroda,

Uehara,

Enomoto

et al. 2024

American J of Med Genetics Pt A

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Lacrimal punctal agenesis is an extremely rare condition with an unclear genetic basis. Here, we report a 3‐year‐old male patient harboring a hemizygous variant in glypican 4 (GPC4), which causes Keipert syndrome, who presented with complete lacrimal punctal agenesis, distinctive craniofacial features, mild developmental delay, mild intellectual disability, and autism. The craniofacial features included a prominent forehead, epicanthus, depressed and broad nasal bridge, hypoplastic columella, midface hypoplasia, tented upper lip, and low‐set ears. Proband exome sequencing identified a hemizygous variant in GPC4: NM_001448.3:c.1051C > T (p.Arg351*). The GPC4 variant was inherited from his heterozygous mother; X‐inactivation followed a skewed pattern in his mother. This patient demonstrated clinical features consistent with Keipert syndrome including craniofacial features, brachydactyly, broad distal phalanx, broad first toe, and mild developmental delay; however, agenesis of the lacrimal puncta has not been reported previously in Keipert syndrome. Our findings suggest that GPC4, which encodes a heparan‐sulfate proteoglycan, may play an important role in lacrimal morphogenesis. Our observations also suggest that Keipert syndrome should be considered in patients with lacrimal punctal agenesis.

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A patient with Keipert syndrome and isolated fibrous dysplasia of the sphenoid sinus

Cited by 4 publications

References 6 publications

Pathogenic Variants in GPC4 Cause Keipert Syndrome

Pathogenic Variants in GPC4 Cause Keipert Syndrome

Fibrous dysplasia of sphenoid bone – diagnostic difficulties

GPC4 truncating variant associated with Keipert syndrome and lacrimal punctal agenesis

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