G C A T T A C G G C A T genes Article The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children Noémi Dahan-Oliel 1,2,* , Klaus Dieterich 3, Frank Rauch 1,2, Ghalib Bardai 1,2, Taylor N. Blondell 4, Anxhela Gjyshi Gustafson 5, Reggie Hamdy 1,2, Xenia Latypova 3, Kamran Shazand 5, Philip F. Giampietro 6 and Harold van Bosse 4,* 1 Shriners Hospitals for Children, Montreal, QC H4A 0A9, Canada; [email protected] (F.R.); [email protected] (G.B.); [email protected] (R.H.) 2 Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 2M1, Canada 3 Inserm, U1216, Grenoble Institut Neurosciences, Génétique médicale, Université Grenoble Alpes, CHU Grenoble Alpes, 38000 Grenoble, France; [email protected] (K.D.); [email protected] (X.L.) 4 Shriners Hospitals for Children, Philadelphia, PA 19140, USA; [email protected] 5 Shriners Hospitals for Children Headquarters, Tampa, FL 33607, USA; [email protected] (A.G.G.); [email protected] (K.S.) 6 Pediatric Genetics, University of Illinois, Chicago, IL 60612, USA; [email protected] * Correspondence: [email protected] (N.D.-O.); [email protected] (H.v.B.) Abstract: Background: Multiple pterygium syndrome (MPS) is a genetically heterogeneous rare form of arthrogryposis multiplex congenita characterized by joint contractures and webbing or pterygia, as well as distinctive facial features related to diminished fetal movement. It is divided into prenatally Citation: Dahan-Oliel, N.; lethal (LMPS, MIM253290) and nonlethal (Escobar variant MPS, MIM 265000) types. Developmental Dieterich, K.; Rauch, F.; Bardai, G.; spine deformities are common, may present early and progress rapidly, requiring regular fo llow-up Blondell, T.N.; Gustafson, A.G.; and orthopedic management. Methods: Retrospective chart review and prospective data collection Hamdy, R.; Latypova, X.; Shazand, K.; were conducted at three hospital centers. Molecular diagnosis was confirmed with whole exome Giampietro, P.F.; et al. The Clinical or whole genome sequencing. Results: This case series describes the clinical features and scoliosis and Genotypic Spectrum of Scoliosis treatment on 12 patients from 11 unrelated families. A molecular diagnosis was confirmed in seven; in Multiple Pterygium Syndrome: A two with MYH3 variants and five with CHRNG. Scoliosis was present in all but our youngest patient. Case Series on 12 Children. Genes The remaining 11 patients spanned the spectrum between mild (curve ≤ 25◦) and malignant scoliosis 2021, 12, 1220. https://doi.org/ (≥50◦ curve before 4 years of age); the two patients with MYH3 mutations presented with malignant 10.3390/genes12081220 scoliosis. Bracing and serial spine casting appear to be beneficial for a few years; non-fusion spinal Academic Editor: Stephen Robertson instrumentation may be needed to modulate more severe curves during growth and spontaneous spine fusions may occur in those cases. Conclusions: Molecular diagnosis and careful monitoring of Received: 18 June 2021 the spine is needed in children with MPS. Accepted: 2 August 2021 Published: 6 August 2021 Keywords: CHRNG; distal arthrogryposis type 8; Escobar; multiple pterygium syndrome; MYH3; scoliosis Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- 1. Introduction iations. The term pterygium is used most commonly to describe an acquired ophthalmologic condition, with a conjunctival “wing” or flap that can cross the cornea. The term also describes joints with congenital webbing or winging of soft tissue which limits the joint motion. Usually, more than one joint and body region is involved, meeting the criteria for Copyright: © 2021 by the authors. arthrogryposis multiplex congenita [1]. While pterygia may be an incidental finding in Licensee MDPI, Basel, Switzerland. persons with arthrogryposis, such as the occasional knee pterygium found associated with This article is an open access article severe contractures in Amyoplasia, they can also manifest as a more generalized syndrome, distributed under the terms and such as popliteal pterygium syndrome or multiple pterygium syndrome (MPS). conditions of the Creative Commons MPS is a rare form of arthrogryposis multiplex characterized by a constellation of Attribution (CC BY) license (https:// congenital anomalies [2]. The webbing of skin and contractures of the joints that are creativecommons.org/licenses/by/ found in this disorder may restrict movement. Examples of joint involvement in the 4.0/). Genes 2021, 12, 1220. https://doi.org/10.3390/genes12081220 https://www.mdpi.com/journal/genes Genes 2021, 12, 1220 2 of 14 MPS is a rare form of arthrogryposis multiplex characterized by a constellation of congenital anomalies [2]. The webbing of skin and contractures of the joints that are found in this disorder may restrict movement. Examples of joint involvement in the upper ex- tremities include axillary pterygia (both the anterior and posterior folds), elbow flexion contractures with antecubital webbing, mildly dorsiflexed wrists, and fingers with camp- todactyly, interdigital pterygia and thumb-in-palm deformities. In the lower extremities, perineal pterygia can span medially from one thigh to the other, knee flexion contractures Genes 2021, 12, 1220 with pterygia can be severe, and foot deformities include both clubfoot and2 of 14 congenital vertical talus (rocker bottom foot). upperOther extremities characteristic include findings axillary pterygia of MPS (both are short the anterior stature, and webbing posterior folds), of the elbow neck, and dis- tinctiveflexion facial contractures features with including antecubital micrognath webbing,ia, mildly cleft dorsiflexed palate, down-turned wrists, and fingers corners of the mouth,with an camptodactyly, elongated philtrum, interdigital down-slanting pterygia and thumb-in-palm palpebral fissures, deformities. epicanthal In the lower folds, ptosis, extremities, perineal pterygia can span medially from one thigh to the other, knee flexion and contractureslow-set ears, with all pterygia of which can beare severe, related and to foot diminished deformities fetal include movement. both clubfoot Developmental and spinecongenital deformities vertical are talus common, (rocker bottom not only foot). as a coronal plane deformity (scoliosis), but fre- quently withOther a characteristic substantial findingsassociated of MPS sagittal are short plane stature, deformity, webbing making of the neck,it a kyphoscoliosis. and Spontaneousdistinctive facialspinal features fusion including abnormalities micrognathia, occur cleft often palate, in down-turnedMPS and are corners congenital. of the mouth, an elongated philtrum, down-slanting palpebral fissures, epicanthal folds, ptosis, andMPS low-set can be ears, separated all of which into are the related lethal to diminishedpterygium fetal syndromes movement. (LMPS, Developmental MIM253290) and the non-lethalspine deformities syndromes; are common, the latter not only conditions as a coronal are plane categorically deformity (scoliosis),referred to but as Escobar syndromefrequently (or with Escobar a substantial variant associated MPS, MIM265000) sagittal plane deformity, and most making are autosomal it a kyphoscoliosis. recessive. Here we willSpontaneous only be spinaldiscussing fusion abnormalitiesthe non-lethal occur forms often of in MPS. MPS and are congenital. SeveralMPS genes can be separatedassociated into with the lethal MPS pterygium give rise syndromes to what has (LMPS, recently MIM253290) been described and as a the non-lethal syndromes; the latter conditions are categorically referred to as Escobar prenatalsyndrome form (or of Escobar myasthenia, variant MPS,first associated MIM265000) with and most variants are autosomal in CHRNG recessive.. CHRNG Here codes for the γwe subunit will only of be the discussing acetylcholine the non-lethal receptor forms (AChR) of MPS. in the developing fetus. Mutations that impact theSeveral expression genes associated of this withsubunit, MPS giveits in risetegration to what hasin the recently AChR, been or described the transport as of the AChRa prenatal to the sarcolemma form of myasthenia, will have first associatedmajor cons withequences variants to in theCHRNG neurom. CHRNGuscularcodes junction. At for the γ subunit of the acetylcholine receptor (AChR) in the developing fetus. Mutations ɛ 33 weeksthat impact gestation the expression though, of the this γ subunit, subunit its starts integration to be in replaced the AChR, by or thethe transport subunit of of AChR, finallythe leading AChR to to the a sarcolemma functional will adult have neuromus major consequencescular junction. to the neuromuscular However, effects junction. of the fetal akinesiaAt 33 have weeks become gestation manifest though, thebeforeγ subunit that stage starts toof bedevelopment replaced by the ande subunitthe damage of is irre- versible.AChR, Interestingly, finally leading individuals to a functional with adult Escobar neuromuscular syndrome junction. do However,not have effects muscle of weakness or electrophysiologicalthe fetal akinesia have becomesymptoms manifest associated before that with stage myasthenia of development gravis and the postnatally, damage as the is irreversible. Interestingly, individuals with Escobar syndrome do not have muscle AChRweakness essentially or electrophysiological functions norm symptomsally after associated birth. Other with myasthenia causes of gravisEscobar