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. 2020 Apr:133:115219.
doi: 10.1016/j.bone.2019.115219. Epub 2020 Jan 7.

Biallelic variants in KYNU cause a multisystemic syndrome with hand hyperphalangism

Nadja Ehmke  1 , Kristina Cusmano-Ozog  2 , Rainer Koenig  3 , Manuel Holtgrewe  4 , Banu Nur  5 , Ercan Mihci  5 , Holly Babcock  6 , Claudia Gonzaga-Jauregui  7 , John D Overton  7 , Jing Xiao  8 , Ariel F Martinez  9 , Maximilian Muenke  9 , Alexander Balzer  10 , Judith Jochim  11 , Naji El Choubassi  12 , Björn Fischer-Zirnsak  12 , Céline Huber  13 , Uwe Kornak  12 , Sarah H Elsea  8 , Valérie Cormier-Daire  13 , Carlos R Ferreira  14
Affiliations

Biallelic variants in KYNU cause a multisystemic syndrome with hand hyperphalangism

Nadja Ehmke et al. Bone. 2020 Apr.

Abstract

Catel-Manzke syndrome is characterized by the combination of Pierre Robin sequence and radial deviation, shortening as well as clinodactyly of the index fingers, due to an accessory ossification center. Mutations in TGDS have been identified as one cause of Catel-Manzke syndrome, but cannot be found as causative in every patient with the clinical diagnosis. We performed a chromosome microarray and/or exome sequencing in three patients with hand hyperphalangism, heart defect, short stature, and mild to severe developmental delay, all of whom were initially given a clinical diagnosis of Catel-Manzke syndrome. In one patient, we detected a large deletion of exons 1-8 and the missense variant c.1282C > T (p.Arg428Trp) in KYNU (NM_003937.2), whereas homozygous missense variants in KYNU were found in the other two patients (c.989G > A (p.Arg330Gln) and c.326G > C (p.Trp109Ser)). Plasma and urine metabolomic analysis of two patients indicated a block along the tryptophan catabolic pathway and urine organic acid analysis showed excretion of xanthurenic acid. Biallelic loss-of-function mutations in KYNU were recently described as a cause of NAD deficiency with vertebral, cardiac, renal and limb defects; however, no hand hyperphalangism was described in those patients, and Catel-Manzke syndrome was not discussed as a differential diagnosis. In conclusion, we present unrelated patients identified with biallelic variants in KYNU leading to kynureninase deficiency and xanthurenic aciduria as a very likely cause of their hyperphalangism, heart defect, short stature, and developmental delay. We suggest performance of urine organic acid analysis in patients with suspected Catel-Manzke syndrome, particularly in those with cardiac or vertebral defects or without mutations in TGDS.

Keywords: Catel-Manzke syndrome; Hyperphalangism; KYNU; Kynureninase deficiency; Skeletal dysplasia; Xanthurenic aciduria.

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Conflict of interest statement

Declaration of competing interest Claudia Gonzaga-Jauregui is a full-time employee of the Regeneron Genetics Center from Regeneron Pharmaceuticals Inc. and receives stock options as part of compensation. All other authors declare that they have no conflict of interest.

Figures

Figure 1.
Figure 1.. Clinical pictures and radiographs of patients 1–3 showing the clinical features of kyruneninase deficiency with hyperphalangism.
(A, B, E) Clinical photographs of Patient 1, showing microretrognathia, highly arched eyebrows and a high palate. (C, D) Photographs and radiographs of the hands of Patient 1. Note the bilateral radial deviation and mild ulnar clinodactyly of the index fingers, due to supernumerary epiphyseal centers at the base of the second proximal phalanges. Photo and radiograph obtained at the age of 10 years. (F, G) Facial photographs of Patient 2. Note narrow forehead, low anterior hairline, full cheeks, and normal chin. (H, I, J) Photographs and radiographs of the hands of Patient 2. Note shortening and radial deviation of the index fingers, due to an accessory ossicle at the base of the second proximal phalanges. The secondary ossification centers represent longitudinally bracketed epiphyses (delta phalanges). Radiographs were taken at the age of 5 weeks (I) and 4 years (J). (K) Radiographs of the spine of Patient 1. Note butterfly vertebrae at T10-T11 (red arrow) and scoliosis. (L) Facial photographs of Patient 3. Note a high anterior hairline, narrow mouth with downturned corners, thin vermilion of the upper and lower lips, and protruding ears. (M) Photograph of the right foot of Patient 3. Note partial cutaneous syndactyly of toes 2 and 3 and small fifth toe nails. (N) Hand photographs of Patient 3 at the age of 5 years. Note shortening, radial deviation and ulnar clinodactyly of the index fingers, short middle fingers with ulnar deviation, and clinodactyly of the fifth fingers. (O) Hand radiographs of Patient 3 at the age of 5 years. Note bilateral supernumerary epiphyseal centers at the ulnar side of the base of the second proximal phalanges and at the radial side of the base of the third proximal phalanges with consequent shortening of third proximal phalanges, severe hypoplasia of the second metacarpals with longitudinally bracketed epiphyses, and hypoplasia of the middle phalanges of the index, third and fifth fingers. (P) Radiographs of the spine of Patient 2. Note butterfly vertebrae at T8 (red arrow).
Figure 2.
Figure 2.. Novel and previously reported human KYNU mutations.
Scheme of KYNU indicating the position of the detected mutations (above) compared to the previously reported mutations (below), and the conservation of the affected amino acid positions for the novel variants.
Figure 3.
Figure 3.. Metabolites in the tryptophan degradation pathway.
Metabolomic profiling revealed a statistically significant elevation in metabolites proximal to the block (3-hydroxykynurenine, xanthurenate, kynurenine) with concomitantly decreased metabolites distal to the block (picolinate, quinolinate). ****, p<0.0001; **, p<0.01.
Figure 4.
Figure 4.. Hypothetical mechanism of hyperphalangism in the setting of kynureninase deficiency.
Names in red indicate enzyme deficiencies associated with hyperphalangism or delta-shaped phalanges, while names in blue indicate enzyme deficiencies associated with other skeletal involvement. Mutations in CANT1 are associated with Desbuquois dysplasia type 1 [41] and consequent hyperphalangism of the index fingers. CANT1 encodes a nucleotidase, the deficiency of which leads to accumulation of UDP, a known inhibitor of multiple glycosyltransferases, in particular those that transfer xylose [–44], galactose [45], and glucuronic acid [46]. IMPAD1 encodes the Golgi-resident PAP-specific 3’-phosphatase (gPAPP), the deficiency of which leads to accumulation of PAP, a known inhibitor of sulfotransferases [41, 47]. gPAPP deficiency is associated with variable hyperphalangism. Mutations in CHSY1, encoding the chondroitin sulfate synthase, are associated with hyperphalangism of digits 1–3 [41]. Note that mutations in the genes encoding the transcription factors ERF and GDF5 also lead to hyperphalangism [48, 49].
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