FAM111A Mutations Result in Hypoparathyroidism and Impaired Skeletal Development Sheila Unger, Maria W. Górna, Antony Le Béchec, Sonia Do Vale-Pereira,

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FAM111A Mutations Result in Hypoparathyroidism and Impaired Skeletal Development Sheila Unger, Maria W. Górna, Antony Le Béchec, Sonia Do Vale-Pereira, Maria Francesca Bedeschi, Stefan Geiberger, Giedre Grigelioniene, Eva Horemuzova, Faustina Lalatta, Ekkehart Lausch, Cinzia Magnani, Sheela Nampoothiri, Gen Nishimura, Duccio Petrella, Francisca Rojas-Ringeling, Akari Utsunomiya, Bernhard Zabel, Sylvain Pradervand, Keith Harshman, Belinda Campos-Xavier, Luisa Bonafé, Giulio Superti-Furga, Brian Stevenson, Andrea Superti-Furga The American Journal of Human Genetics Volume 92, Issue 6, Pages 990-995 (June 2013) DOI: 10.1016/j.ajhg.2013.04.020 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 Phenotypic Features of KCS and OCS (A) Individual 1 (c.1706G>A [p.Arg569His]) at age 8 years. Note short stature (95 cm) and frontal bossing with a triangular face and small eyes. (B and C) Radiographs of individual 2 (c.1706G>A [p.Arg569His]) at age 14 years. The arrowheads indicate the increased thickness of the cortical bone (B) and the narrowing of the medullary cavity of tubular bones (C) (diaphyseal stenosis). (D) Skull radiograph of individual 1 at age 25 years. Note V-shaped orbital roofs (secondary to basal craniosynostosis; compare to F) and extensive dental prosthetization. (E) Facial appearance of individual 7 (c.1026_1028delTTC [p.Ser342del]) at a few days of age. Note frontal bossing, bitemporal narrowing with supra-auricular bulging, low-set ears, and small, deep-set eyes; compare to (A). (F) Skull radiograph of individual 6 (c.1026_1028delTTC [p.Ser342del]). There is hypomineralization of the cranial vault, and the configuration of the orbital region indicates basal craniosynostosis (compare to D). (G) Babygram of individual 6. The skeletal elements have a dense appearance. The long bones are thin, and the medullary cavity is not recognizable (“osteostenosis”). (H) Simplified scheme of FAM111A. The green domain has homology to trypsin-like peptidases, and the residues indicated in blue constitute the conserved putative catalytic triad. The changes predicted by the mutations observed in individuals with KCS and OCS are indicated in orange (KCS) and red (OCS). The American Journal of Human Genetics 2013 92, 990-995DOI: (10.1016/j.ajhg.2013.04.020) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 Skeletal Pathology of an OCS-Affected Newborn, Case 7, Who Died at Age 25 Days (A) Macroscopic view of the left femur. Note the thin diaphysis with splayed metaphyses. The cartilagineous epiphyses appear macroscopically normal. Compare with the radiographic appearance in Figure 1G. (B) Representative view of the growth-plate architecture at the proximal femur (magnification is approximately 200×). The overall architecture is preserved. The chondrocyte columns are slightly shorter and plumper than normal, and most of them have a polyclonal rather than monoclonal appearance. The inset (magnification is approximately 4×) shows the localization of the larger panel on the whole mount. (C) Representative view of the diaphyseal cortex of the femur (magnification is approximately 200×); the inset (magnification is approximately 4×) shows the localization of the larger panel on the whole mount. The cortical bone is thicker than normal (as also appreciable on the radiographs). The bone trabeculae are thicker, and the lacunae are reduced. The osteoid lamellae have an unusual wavy appearance. These findings correlate well with the findings in parathyroid hormone (PTH)-ablated mice.9 The American Journal of Human Genetics 2013 92, 990-995DOI: (10.1016/j.ajhg.2013.04.020) Copyright © 2013 The American Society of Human Genetics Terms and Conditions