Principles of the differential diagnosis of achondroplasia and pseudoachondroplasia

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Abstract

BACKGROUND: Achondroplasia and pseudoachondroplasia are hereditary systemic skeletal dysplasias characterized by a certain similarity of clinical manifestations; however, they have different etiopathogenetic mechanisms and confirmation methods for molecular genetic diagnosis. Their common phenotypic features often make differential diagnosis difficult during the clinical examination of patients, planning DNA diagnostics, and appropriate time detection of neurosurgical and orthopedic complications.

AIM: This study aimed to identify differential diagnostic criteria for achondroplasia and pseudoachondroplasia and optimize the strategy for their molecular genetic diagnosis.

MATERIALS AND METHODS: A comprehensive examination of 76 children from 74 unrelated families aged 1 month to 18 years with phenotypic signs of achondroplasia and pseudoachondroplasia was conducted. To clarify the diagnosis through genealogical and amnestic analysis, clinical and neurological examination data according to the standard method and radiographic data were used. Molecular genetic confirmation of diseases was conducted by searching for hotspot mutations in the FGFR3 gene, assessing the number of GAC repeats located in exon 13 of the COMP gene, and new-generation sequencing of the target panel consisting of 166 genes responsible for hereditary skeletal pathology.

RESULTS: Based on a comparative analysis of the specific phenotypic characteristics, the criteria for the differential diagnosis of achondroplasia and pseudoachondroplasia were identified. The leading signs of achondroplasia are disproportionate nanism from birth, macrocrania, and facial dysmorphism, which are not specific to pseudoachondroplasia. Certain radiological features are essential in the differential diagnosis of pseudoachondroplasia, which should be considered when referring to patients for molecular genetic analysis. A deletion of the GAC repeat c.1417_1419del in the COMP gene was identified in 27% of patients with pseudoachondroplasia. Thus, the analyses of these two mutations in FGFR3 and COMP were conducted first. In the absence of target mutations, further diagnostic search should be continued with a target panel consisting of 166 genes responsible for hereditary skeletal pathology or whole-exome sequencing.

CONCLUSIONS: The analysis of the clinical, radiological, and molecular genetic characteristics of patients with achondroplasia and pseudoachondroplasia, together with the literature data analysis, made it possible to clarify the differential diagnostic criteria for these diseases and optimize the algorithm for their molecular genetic diagnosis.

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
Scopus Author ID: 57204436561
ResearcherId: AAJ-8352-2021

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

Russian Federation, Moscow

Vladimir M. Kenis

H. Turner National Medical Research Center for Сhildren’s Orthopedics and Trauma Surgery; North-Western State Medical University named after I.I. Mechnikov

Email: kenis@mail.ru
ORCID iD: 0000-0002-7651-8485
SPIN-code: 5597-8832
Scopus Author ID: 36191914200
ResearcherId: K-8112-2013
http://www.rosturner.ru/kl4.htm

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

Russian Federation, Saint Petersburg; Saint Petersburg

Evgenii V. Melchenko

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

Email: emelchenko@gmail.com
ORCID iD: 0000-0003-1139-5573
SPIN-code: 1552-8550
Scopus Author ID: 55022869800

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

Russian Federation, Saint Petersburg

Dmitry A. Reshchikov

Russian Children’s Clinical Hospital of the Russian National Research Medical University named after N.I. Pirogov

Email: reshchikovdm@gmail.com
ORCID iD: 0000-0001-8146-5501
SPIN-code: 4821-5487

Neurosurgeon

Russian Federation, Moscow

Aynur E. Alieva

Research Centre for Medical Genetics

Email: alieva.aynur1996@gmail.com
ORCID iD: 0000-0003-1048-075X

Resident Doctor

Russian Federation, Moscow

Darya V. Osipova

Research Centre for Medical Genetics

Email: osipova.dasha2013@yandex.ru
ORCID iD: 0000-0002-5863-3543
SPIN-code: 9835-9616
Scopus Author ID: 57218497500
ResearcherId: AAA-6909-2022

MD, Geneticist

Russian Federation, Moscow

Liudmila A. Bessonova

Research Centre for Medical Genetics

Email: bessonovala@yandex.ru
ORCID iD: 0000-0002-5946-4577

MD, Geneticist

Russian Federation, Moscow

Tatiana S. Nagornova

Research Centre for Medical Genetics

Email: t.korotkaya90@gmail.com
ORCID iD: 0000-0003-4527-4518
SPIN-code: 6032-2080

MD, Laboratory Geneticist

Russian Federation, Moscow

Natalya N. Vasserman

Research Centre for Medical Genetics

Email: vasserman@dnalab.ru
ORCID iD: 0000-0001-5007-6028
SPIN-code: 2936-7200

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

Russian Federation, Moscow

Natalya Yu. Ogorodova

Research Centre for Medical Genetics

Email: ognatashka@mail.ru
ORCID iD: 0000-0001-6151-5022
SPIN-code: 4300-7904

MD, Laboratory Geneticist

Russian Federation, Moscow

Olga A. Shchagina

Research Centre for Medical Genetics

Email: schagina@dnalab.ru
ORCID iD: 0000-0003-4905-1303
Scopus Author ID: 25422833100
ResearcherId: W-4835-2018

MD, PhD, Cand. 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
Scopus Author ID: 6701733307
ResearcherId: AFG-0883-2022

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

Russian Federation, Moscow

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2. Fig. 1. Appearance of patients with achondroplasia (a, b) and pseudoachondroplasia (c, d). Both patients have a disproportionate short stature with limb shortening, chest deformity, incomplete extension of elbow joints, lower extremity deformities, and brachydactyly, and macrocrania (an increase in cranial size and frontal and parietal protuberances) and facial dysmorphism (midface hypoplasia) were noted only in a patient with achondroplasia

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3. Fig. 2. Appearance of the hands of patients with achondroplasia (a) and pseudoachondroplasia (b): both patients had brachydactyly. Isodactyly (comparable length of fingers) and ectrosyndactylia symptoms (divergence of the phalanges of the fingers, more pronounced between the terminal phalanges of the fingers II–III and III–IV) were noted only in a patient with achondroplasia

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4. Fig. 3. Radiographs of the thoracic and lumbar spine in the lateral view of patients with achondroplasia (a) and pseudoachondroplasia (b): a, physiological ossification of the apophyses of the vertebral bodies with square contours of the vertebrae (white arrows), flattened thoracic kyphosis (yellow line), pathological thoracolumbar kyphosis (red line), and enhanced lumbar lordosis (blue line); b, abnormal ossification of the apophyses of the vertebral bodies with linguiform protrusions of the anterior parts of the vertebrae (white arrows), physiological value of thoracic kyphosis (yellow line), and moderate increase in lumbar lordosis (blue line)

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5. Fig. 4. Radiographs of the hip joints and femoral bones in the frontal view of patients with achondroplasia (a) and pseudoachondroplasia (b): a, horizontal position of the acetabular hood (white line), narrowed sciatic notch (white arrow), ectrosyndactylia (black arrows), and square outlines of the iliac wings (white outline); b, skewness of the acetabular hood (white lines) and oval outlines of the iliac wings (white outline)

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6. Fig. 5. Radiographs of the hands of a patient with achondroplasia (a) and pseudoachondroplasia (b): moderate ulnar deviation of the hand and brachydactyly in both patients (marked with a white outline), and shortening of the metacarpal bones with scyphoid expanded metaphyses, and small rounded ball-in-socket epiphyses in patients with pseudoachondroplasia (white arrows)

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7. Fig. 6. Domain-specific distribution of pathogenic variants in COMP. Newly identified variants in COMP are highlighted in red, previously described variants are highlighted in blue, and frequent mutations are highlighted in green

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Copyright (c) 2023 Markova T.V., Kenis V.M., Melchenko E.V., Reshchikov D.A., Alieva A.E., Osipova D.V., Bessonova L.A., Nagornova T.S., Vasserman N.N., Ogorodova N.Y., Shchagina O.A., Dadali E.L.

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