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Vol. 82. Issue 6.
Pages 436-439 (01 June 2015)
Vol. 82. Issue 6.
Pages 436-439 (01 June 2015)
Scientific Letter
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Clinical and molecular diagnostics of a cartilage-hair hypoplasia: Two new cases
El diagnóstico clínico-molecular en la hipoplasia de cartílago-pelo: dos nuevos casos
M. Fenollar-Cortésa,b,
Corresponding author
, E. Lara-Orejasc, A. González-Menesesd, J.L. Ruibal-Franciscoc, M.J. Trujillo-Tiebasb,e
a Sección de Genética Clínica, Servicio de Análisis Clínicos, Hospital Clínico San Carlos, Madrid, Spain
b Servicio de Genética, IIS-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain
c Departamento de Pediatría, Hospital Infanta Cristina, Parla, Madrid, Spain
d Unidad de Dismorfología, Servicio de Pediatría, Hospital Universitario Virgen del Rocío, Sevilla, Spain
e Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
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Table 1. Differential diagnosis of cartilage-hair hypoplasia.
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Dear Editor:

The diagnosis of cartilage-hair hypoplasia, also known as McKusick type metaphyseal chondrodysplasia (OMIM 250250), is based on disproportionate short stature, bowed femurs and tibias, short and broad phalanges, loose ligaments with characteristic incomplete extension of the elbows and sparse hair, and was first described in the Amish population of the United States.1 It is caused by mutations in the RMRP gene (OMIM 157660; 9p13),2 a nuclear noncoding gene for an RNA chain that is a subunit of the mitochondrial RNase MRP protein complex, which is involved in ribosomal assembly and cellular cycle regulation. The disorder has a recessive pattern of inheritance, and depending on the severity of the mutation it can have a broad range of clinical manifestations (from mild to severe): metaphyseal dysplasia without hypotrichosis, cartilage-hair dysplasia and anauxetic dysplasia.3

Case 1

Boy, 7 months of age, with healthy nonconsanguineous Spanish parents. He was born at 40 weeks, with a weight of 3200g, length of 45cm and head circumference of 36cm. He was admitted at 4 months of age with acute gastroenteritis. The physical examination revealed sparse, fine and brittle hair, shortened limbs, moderate varus bowing of the femurs, and short fingers. His height was 65.5cm (−1.31SD) and his weight 7850g (−0.72SD). Bone radiography showed shortening of long bones and metaphyseal widening. Immunologic testing showed moderate neutropaenia and lymphocytopaenia (reduced T CD4+ and B+T cells); low levels of IgA and normal IgM and IgG levels. These findings led to a clinical diagnosis of cartilage-hair hypoplasia. An RMRP test was ordered at 3 years of age, which detected the presence of 2 heterozygous mutations [g.236A>G, paternal; g.260G>A, maternal]. This diagnosis allowed for screening the maternal blood for the paternal mutation in the foetal DNA (noninvasive prenatal technique) at 8 and 10 weeks in the 2 subsequent gestations of this couple. In the first of these pregnancies, the paternal mutation in the foetal DNA was detected in maternal blood and confirmed by amniocentesis (invasive technique). The pregnancy was terminated. The paternal mutation was not detected in the second pregnancy, and this finding was confirmed by an invasive prenatal test (healthy noncarrier foetus, publication in progress). At 9 years of age, the patient still has short stature (height 108cm [−4.06SD]; weight 20kg [−2.25SD]), and moderate varus bowing of the limbs with followup in the rehabilitation department. His hair is sparse. The patient has had 2 episodes of pneumonia in which no pathogen was identified. His vaccinations are up to date with the immunisation schedule of his autonomous community, and the patient had mild febrile reactions to live virus vaccines. The patient is receiving prophylaxis with trimethoprim-sulfamethoxazole 3 days a week (Fig. 1).

Figure 1.

Top: case 1 patient at 9 and 18 months, and at 5 and 7 years, respectively. Mutations found in the RMRP gene. Bottom: case 2 patient at 4.5 years of age and radiographs at 2 years of age.

Case 2

Boy aged 2.3 years of Romanian descent diagnosed with achondroplasia at one week of life. The parents were nonconsanguineous, the pregnancy was monitored in Romania, and the patient was born to term; the birth anthropometric measurements are not known. Physical examination showed a height of 62cm (−9.6SD), weight of 8620g (−3.34SD), shortening of upper and lower extremities, thick hands and short fingers. There were no skull abnormalities, and the hair was sparse, very fine and blonde. Bone radiography showed short hand bones with cone-shaped epiphyses, knees with broad and irregular metaphyses and poorly ossified epiphyses, femoral bowing with delayed ossification of the proximal femoral epiphyses, and hip bones with normal acetabula (Fig. 1). Laboratory tests were performed (complete blood count, biochemistry panel, and immunoglobulins) the results of which were normal. At 7.4 years of age he was 90.6cm tall (−6.2SD), had a growth rate of 4–7cm a year (−2.1SD and −1.4SD), he had not developed any severe infections or any type of gastrointestinal malabsorption. We ordered a direct RMRP gene test that revealed 2 heterozygous mutations (g.96_97dupTG, maternal; g.-25-11 dupACTACTCTGTGAAGC). The father did not cooperate (Fig. 1).

The mutations found in these 2 cases have been described previously in patients of European descent with a cartilage-hair hypoplasia phenotype.4 The g.-25-11 dupACTACTCTGTGAAGC mutation in the Romanian patient has been described in a patient of Spanish descent.5Table 1 shows the differential diagnosis. A full diagnosis based on clinical and molecular findings can help predict the prognosis of the disease and inform its management. Immune function, both humoral (IgG deficiency) and cellular (lymphocytopaenia), and the presence of nonregenerative macrocytic anaemia should be evaluated. These patients may also develop malignancies, especially of the blood (lymphomas and leukaemia).6 Possible treatments include osteostomies to correct deformities, surgical bone lengthening, infection prophylaxis in the presence of an immunodeficiency, and prophylactic treatment for anaemia, should it develop. Molecular diagnosis makes it possible to provide adequate genetic counselling for family planning and reproductive health.

Table 1.

Differential diagnosis of cartilage-hair hypoplasia.

  Cartilage-hair hypoplasia  Kyphomelic dysplasia  Immunoosseous dysplasia, Schimke type  Omenn syndrome  Skeletal dysplasia with severe combined immunodeficiency  Shwachman–Diamond syndrome 
OMIM  250250  211350  242900  603554  200900  260400 
Gene  RMRP  Unknown  SMARCAL1  DCLRE1C, RAG1, RAG2  Unknown  SBDS 
Location  9p13  Unknown  2q35  11p12,10’13  Unknown  7q11 
Inheritance  AR  AR  AR  AR  AR  AR 
Skeletal abn.  POS  POS  POS  NEG  POS  POS 
Type  Metaphyseal  Metaphyseal  Spondyloepiphyseal  –  Metaphyseal  Metaphyseal 
Bowed femur and tibia  POS  POS  NEG  NEG  NEG  NEG 
Short stature  POS  POS  POS  NEG  POS  POS 
  Disproportionate  Disproportionate  Disproportionate  Growth failure  Disproportionate   
Haematological abn.  POS  NEG  POS  POS  POS  POS 
Type  Lymphocytopaenia, neutropaenia, risk of malignancy    Lymphocytopaenia, neutropaenia, thrombocytopaenia  Eosinophilia, thrombocytopaenia  Lymphocytopaenia  Pancytopaenia, risk of malignancy 
Anaemia  Frequent  NEG  POS  POS  NEG  POS 
Hair  Thin, sparse and blonde eye brows and lashes  Normal  Fine  Alopecia  Normal  Normal 
Immunological abn.  POS  NEG  POS  POS  POS  NEG 
Type  ↓ T and B cells    ↓ T cells  Lymphadenopathy, architectural effacement of lymph nodes,↓ B cells  Agammaglobulinaemia, thymic hypoplasia   
Gastrointestinal abn.  POS  NEG  NEG  NEG  NEG  POS 
Type  Gastrointestinal malabsorption, Hirschprung disease, oesophageal atresia          Exocrine pancreatic insufficiency 
Kidney abn.  NEG  NEG  POS  NEG  NEG  NEG 
Type      Progressive nephropathy, rapid and fatal       
Intellectual disability  NEG  NEG  NEG but described  NEG  Unknown  POS 
Life expectancy  Adulthood  Adulthood  Childhood  Childhood  Infancy  Adulthood 

Abn.: abnormality; AR: autosomal recessive; NEG: negative; POS: positive.


We want to thank the laboratory technicians, Jesús Gallego Merlo and Camilo Vélez Monsalve, for their invaluable daily work and their contribution to the diagnosis of these 2 cases. We thank the patients and their families for consenting to the publications of images and clinical data for scientific purposes.

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High-resolution linkage-desequilibrium mapping of the cartilage-hair hypoplasia gene.
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Please cite this article as: Fenollar-Cortés M, Lara-Orejas E, González-Meneses A, Ruibal-Francisco JL, Trujillo-Tiebas MJ. El diagnóstico clínico-molecular en la hipoplasia de cartílago-pelo: dos nuevos casos. An Pediatr (Barc). 2015;82:436–439.

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