Clinical and genetic characteristics of multicentric carpotarsal osteolysis syndrome

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Abstract

BACKGROUND: Multicentric carpotarsal osteolysis (MCTO) syndrome is a rare autosomal dominant disease of skeletal dysplasias caused by heterozygous missense variants in MAFB. Clinical manifestations of the disease are characterized by pain, swelling, and hand and foot deformities as a result of progressive osteolysis of the carpal and tarsal bones. Kidney insufficiency also developed in some patients.

CLINICAL CASES: Three Russian patients aged 2–39 years with MCTO syndrome caused by pathogenic variants c.176C>T, c.184A>G, c.203C>T in MAFB are presented. All cases were sporadic. Two of our patients with MCTO were typically observed for several years with a diagnosis of juvenile idiopathic arthritis. All patients underwent phenotypic analysis using standard methods, radiography of the upper and lower extremities, ultrasonography of the kidneys, blood and urine tests to assess renal function, and molecular tests to clarify the diagnosis. Molecular genetic analysis included direct automatic Sanger sequencing of MAFB (NM_005461.5).

DISCUSSION: The clinical manifestations of the disease in the patients included deformities and shortening of the hands and feet and typical signs of osteolysis of the metacarpal and metatarsal bones on radiographs. One of the examined patients had proteinuria in early childhood. Considering the rarity of MCTO syndrome, a description of the clinical and radiological characteristics of newly identified cases of the disease will help optimize its diagnosis and multidisciplinary observation of patients and improve the quality of medical and genetic counseling for affected families.

CONCLUSIONS: The first clinical manifestations of MCTO syndrome are characterized by significant similarities with those of juvenile arthritis. For their differential diagnosis, a thorough radiographic analysis of the hands and feet for osteolysis is necessary. Early diagnosis of MCTO syndrome is essential because in recent years intensive research aimed at developing therapy for diseases caused by dysfunction of the RANK/RANKL signaling pathway, in which the protein product of MAFB functions.

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About the authors

Tatiana V. Markova

Research Centre for Medical Genetics

Email: markova@med-gen.ru
ORCID iD: 0000-0002-2672-6294
SPIN-code: 4707-9184

MD, PhD, Dr. Sci. (Med.)

Russian Federation, Moscow

Vladimir М. Kenis

H. Turner National Medical Research Center for Children’s Orthopedics and Trauma Surgery

Email: kenis@mail.ru
ORCID iD: 0000-0002-7651-8485
SPIN-code: 5597-8832

MD, PhD, Dr. Sci. (Med.), Professor

Russian Federation, 64-68 Parkovaya str., Pushkin, Saint Petersburg, 196603

Aleksei N. Kozhevnikov

H. Turner National Medical Research Center for Children’s Orthopedics and Trauma Surgery

Email: infant_doc@mail.ru
ORCID iD: 0000-0003-0509-6198
SPIN-code: 1230-6803

MD, PhD, Cand. Sci. (Med.)

Russian Federation, 64-68 Parkovaya str., Pushkin, Saint Petersburg, 196603

Yuriy V. Buklemishev

Priorov Central Institute for Trauma and Orthopedics

Email: buklemishev@mail.ru
ORCID iD: 0000-0002-0039-2118
SPIN-code: 4329-4720

doctor of the Counselling and Diagnostic Department

Russian Federation, Moscow

Darya V. Gorodilova

Research Centre for Medical Genetics

Email: osipova.dasha2013@yandex.ru
ORCID iD: 0000-0002-5863-3543
SPIN-code: 9835-9616

MD, geneticist

Russian Federation, Moscow

Olga А. Shchagina

Research Centre for Medical Genetics

Email: schagina@dnalab.ru
ORCID iD: 0000-0003-4905-1303
SPIN-code: 9491-2411

MD, PhD, Dr. Sci. (Med.)

Russian Federation, Moscow

Elena L. Dadali

Research Centre for Medical Genetics

Author for correspondence.
Email: genclinic@yandex.ru
ORCID iD: 0000-0001-5602-2805
SPIN-code: 3747-7880

MD, PhD, Dr. Sci. (Med.), Professor

Russian Federation, Moscow

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2. Fig. 1. Clinical manifestations of multicentric carpotarsal osteolysis in patient 1: a, appearance of the patient: severe muscle hypotonia, forced posture (sitting), additional support on the arms, kyphotic posture, funnel chest deformity; typical facial features with round shape, micrognathia, widely spaced round eyes; b, the patient’s hands, relative shortening of the wrists, ulnar deviation of the hands, defiguration of the interphalangeal joints, and flexion deformities of the fingers; c, the patient’s feet, varus position, adduction of the forefoot, shortening of the first rays, and relative shortening of the hind and middle feet

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3. Fig. 2. Clinical manifestations of multicentric carpotarsal osteolysis in patient 2: a, appearance in a standing position: flexion contractures in the elbow and knee joints, winged scapula, increased thoracic kyphosis and lumbar lordosis, varus position of the feet, and facial appearance with dysmorphic features characteristic of multicentric carpotarsal osteolysis (i.e., round shape, micrognathia, and widely spaced round eyes); b, appearance of the hands: ulnar deviations, expansion and defiguration of the wrist, metacarpophalangeal and proximal interphalangeal joints, and flexion deformities of the fingers; c, appearance of the feet: varus position of the hindfeet, forefoot adduction, shortening of the first rays, and general shortening of the feet

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4. Fig. 3. Clinical manifestations of multicentric carpotarsal osteolysis of the hands and feet in patient 3: a, appearance of the hands: increased volume and defiguration of the wrist joints, proximal interphalangeal joints; deformity of the fingers with a visible increase in the volume of soft tissues caused by bone shortening; flexion deformities and lateral deviations of the fingers; b, appearance of the patient’s feet: varus position of the hindfeet, adduction of the forefeet, and shortening of the first toes

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5. Fig. 4. Radiographs of the hands in a frontal view of patients 1 (a), 2 (b), and 3 (c). Shortening of the wrist (red arrows) with decreasing distance between the radial bone and bases of the metacarpal bones, wrist bones osteolysis (blue arrows), decreased height of the radial epiphysis (black arrows), ulnar shortening (white arrows), ulnar deviation (yellow arrows), and osteolytic changes at the bases of the metacarpal bones (green arrows)

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6. Fig. 5. Radiographs of the feet in the frontal view of patients 1 (a), 2 (b), and 3 (c). Osteolysis of the tarsal bones, mainly of the medial column, scaphoid, and first sphenoid (blue arrows); osteolytic changes in the hindfoot bones, mainly in the talus (white arrow); varus deformity and forefoot adduction caused by the shortening of the medial column bones (yellow arrows); and osteolytic changes at the bases of the metatarsal bones (green arrows). Partial osteolysis and reduction in the height of the tibial epiphysis (black arrows)

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7. Fig. 6. Pathogenic MAFB variants in patients with multicentric carpotarsal osteolysis. Top: DNA sequence electrophoregrams indicating the heterozygous MAFB variant for each patient. Bottom: MafB protein with the number of amino acids and protein domains (blue is the transactivation domain). The region containing the pathogenic variants is enlarged, and its nucleotide and amino acid sequences are presented (the figure is based on N.S. Ma et al., 2023 [27])

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