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Cartilage Hair Hypoplasia

Mckusick's Metaphyseal Chondrodysplasia Syndrome

Cartilage hair hypoplasia is a rare multisystemic genetic disorder demarcated by a short stature from birth, hypoplastic hair, various skeletal abnormalities and a variable degree of immunodeficiency that can be fatal in the absence of an early diagnosis. Clinical signs, results from imaging studies, and genetic testing are necessary parts of the diagnostic workup.


Presentation

Signs and symptoms of cartilage hair hypoplasia (CHH) may be evident from birth, when disproportionately short limbs, considered as a cardinal feature of CHH, are identified [1] [2]. Consequently, a short stature is evident in all patients, with metaphyseal dysplasia being the principal pathological event [2] [3]. Bowing of the lower extremities, a prominent reduction in the length of the tibia compared to the fibula, very short hands characterized by increased laxity of the metacarpal, interphalangeal and phalangeal joints, and incomplete extension of the elbow joint are important additional skeletal manifestations of CHH [2] [3]. Apart from growth abnormalities, the appearance of a fine, light-colored and sparse, short hair is the second main component of the clinical presentation [2]. Hypopigmentation of the skin and nail dysplasia can be identified in some cases [4]. Immunodysfunction, humoral and/or cell-mediated, is readily observed, ranging from mild subclinical forms to severe combined immunodeficiency (SCID) [2] [3]. In fact, neutropenia and lymphopenia frequently create favorable conditions for recurrent infections, seen in up to 60% of patients, and are the principal causes of death in CHH [3]. Gastrointestinal conditions, such as malabsorption, celiac disease or Hirschsprung's disease are identified in about 18% of cases, which may be one of the contributing factors for failure of infants to thrive throughout childhood, another possible symptom [4]. Finally, immunodeficiency combined with anemia that is commonly noted shows a significant predilection toward hematologic malignancies, especially lymphomas [2] [3].

Short Stature
  • We report a child with short stature since birth who was otherwise well, presenting at 2.8 years with progressive granulomatous skin lesions when diagnosed with severe T cell immunodeficiency.[ncbi.nlm.nih.gov]
  • We conclude that recessive metaphyseal dysplasia without hypotrichosis is a variant of CHH, manifesting only as short stature and metaphyseal dysplasia.[ncbi.nlm.nih.gov]
  • Imaging studies are used to distinguish CHH from numerous other causes of short stature.[symptoma.com]
  • Cartilage-hair hypoplasia (CHH) is an autosomal recessive metaphyseal chondrodysplasia characterized by severe short-limb short stature and hypoplastic hair.[ncbi.nlm.nih.gov]
  • Cartilage-hair hypoplasia (CHH) is an autosomal recessive disorder characterized by short stature, hypoplastic hair and humoral immunity disorders. It is a mutation in the RMRP gene, located on chromosome 9p13.3, that leads to CHH.[ncbi.nlm.nih.gov]
Anemia
  • Anemia is seen in over 80% of patients with cartilage-hair hypoplasia (CHH). While this is usually mild and self-limited, some patients demonstrate a severe, persistent anemia resembling that seen in Diamond-Blackfan anemia (DBA).[ncbi.nlm.nih.gov]
  • Retrospective analysis of hematological data of 114 patients showed that the severity of the anemia and macrocytosis in CHH varies with age. The anemia was most severe in early childhood.[ncbi.nlm.nih.gov]
  • We did not observe an anemia phenotype.[dukespace.lib.duke.edu]
  • To evaluate the severity of iron overload and the success of iron chelation therapy in patients with cartilage-hair hypoplasia (CHH) and hypoplastic anemia, with particular focus on adverse effects of iron chelators.[ncbi.nlm.nih.gov]
  • Patients with severe hypoplastic anemia require repeated transfusions. Bone marrow transplantation may be required for patients with severe combined immunodeficiency or severe persistent hypoplastic anemia.[ingentaconnect.com]
Recurrent Infection
  • In fact, neutropenia and lymphopenia frequently create favorable conditions for recurrent infections, seen in up to 60% of patients, and are the principal causes of death in CHH.[symptoma.com]
  • It is characterized by disproportionate short stature, fine sparse hair, ligamentous laxity, hematological abnormalities with anemia, a predisposition to malignant tumors, and recurrent infections usually due to cellular and/or humoral immunodeficiency[ncbi.nlm.nih.gov]
  • Data for 5 additional patients with recurrent infections were retrospectively reviewed. Seven of the prospectively evaluated patients (35%) had defective humoral immunity. Three patients had IgA deficiency.[ncbi.nlm.nih.gov]
  • Despite mutation homogeneity, eight (32%) patients had severe or recurrent infections, two (8%) of these children underwent bone-marrow transplantation for combined immunodeficiency, and the remainder were healthy.[ncbi.nlm.nih.gov]
  • Three of the 4 patients suffered from recurrent infections; 1 developed progressive bronchiectasis and another died from aggressive lymphoma. Our findings expand the phenotypic variability in CHH to include normal childhood height.[ncbi.nlm.nih.gov]
Short Stature in Children
  • Growth hormone was used with conflicting results for short stature in children with Cartilage-hair hypoplasia. Skeletal problems must be managed with physiotherapy and appropriate orthopedic interventions.[ingentaconnect.com]
  • These include idiopathic GH deficiency, organic GH deficiency due to a variety of causes such as congenital malformations and syndromes, genetic disorders or treatment for leukaemia or central nervous system tumours and short stature in children born[books.google.com]
Hodgkin's Disease
  • Hensley MF (1984) McKusick's dwarfism and resistant Hodgkin's disease (letter). J Am Osteopath Ass 84:159 PubMed Google Scholar 9.[link.springer.com]
  • Wilson suggested Hodgkin's disease , but Dr. Cameron thought it was an autoimmune disorder and suggested steroids for lupus . However, Dr.[house.wikia.com]
Microdontia
  • In some cases, affected infants may also exhibit improper intestinal absorption of certain necessary nutrients (malabsorption) and/or dental abnormalities such as unusually small teeth (microdontia).[webmd.com]
Hair Hypoplasia
  • hair hypoplasia after hematopoietic stem cell transplantation. ( 20375313 ) Bordon V....Tayfun G. 2010 31 Novel mutation in boy with cartilage-hair hypoplasia. ( 21146796 ) Lin I.C....Wang T.J. 2010 32 An infant with cartilage-hair hypoplasia due to[malacards.org]
  • Cartilage Hair Hypoplasia: What You Need to Know Cartilage hair hypoplasia is a hereditary condition. Cartilage hair hypoplasia is commonly found in the Amish community.[hopkinsmedicine.org]
  • Skeletal growth in cartilage-hair hypoplasia. A radiological study of 82 patients. Pediatr Radiol. 1992;22:434-39. Makitie O, et al. Growth in cartilage-hair hypoplasia. Pediatr Res. 1992;31:176-80. Makitie O, et al.[rarediseases.org]
  • Cartilage Hair Hypoplasia Treatment Treatment of Cartilage Hair Hypoplasia is symptomatic depending on an individual’s features of the disorder. Treatment may include medications to fight infections (e.g.[evolvegene.com]
  • Thus, immunodeficiency in individuals with cartilage-hair hypoplasia varies, often with limited susceptibility to infections, and many children with cartilage-hair hypoplasia may live healthy lives.[emedicine.medscape.com]
Sparse Hair
  • Cartilage-hair hypoplasia (CHH) is a rare autosomal-recessive disorder characterized by short-limbed dwarfism, sparse hair, and immune deficiency.[ncbi.nlm.nih.gov]
  • Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive skeletal dysplasia characterized by short stature, sparse hair, and a variable degree of immunodeficiency.[ncbi.nlm.nih.gov]
  • Cartilage hair hypoplasia (CHH) is an autosomal recessively inherited syndrome characterized by short stature, sparse hair, and immunodeficiency.[ncbi.nlm.nih.gov]
  • It is characterized by disproportionate short stature, fine sparse hair, ligamentous laxity, hematological abnormalities with anemia, a predisposition to malignant tumors, and recurrent infections usually due to cellular and/or humoral immunodeficiency[ncbi.nlm.nih.gov]
  • Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive short-limbed dwarfism associated with thin and sparse hair and cell mediated or combined immunodeficiency. However, the basis of immune deficiency in CHH is unclear.[ncbi.nlm.nih.gov]
Skin Lesion
  • We report a child with short stature since birth who was otherwise well, presenting at 2.8 years with progressive granulomatous skin lesions when diagnosed with severe T cell immunodeficiency.[ncbi.nlm.nih.gov]
  • Pre-existing autoimmunity and inflammatory skin lesions were a prominent feature in 5 of 16 patients (patient nos. 3, 5, 8, 11, and 12; Table 1 ). Thirteen patients were transplanted in early childhood (mean age 2.5 years).[bloodjournal.org]
Hypopigmented Skin
  • Additional findings may include Hirschsprung disease, hypopigmented skin, various defects of cellular immunity and anemia. Metaphyseal dysplasia without hypotrichosis (CHHV) is an autosomal recessive disorder recognized as a variant of CHH.[ctgt.net]
Lordosis
  • Increased ligamentous laxity was present in 95%, limited extension of the elbows in 92%, increased lumbar lordosis in 85%, thoracal deformity in 68%, genu varum in 63% and scoliosis in 21% of the patients.[ncbi.nlm.nih.gov]
  • Lumbar lordosis was moderately increased. Thoracic deformity was observed in 82% of the patients. The relative interorbital distance was increased with the median of 2.2 SD in the adults.[ncbi.nlm.nih.gov]
  • […] peptide (PTHRP) receptor mental retardation short limbed dwarfism wide eyes monkey like stance ostebulbous metaphyseal expansion of long bones seen on xray Schmid's autosomal dominant defect in Type X collagen short limbed dwarfism excessive lumbar lordosis[orthobullets.com]
  • Lumbar lordosis is increased ( 11 ).[jpediatricsreview.com]
Short Arm
  • We have previously mapped the gene for CHH to the short arm of chromosome 9 in Finnish and Amish families. The CHH locus resides close to D9S163 within an interval of 1.5 cM flanked by D9S165 and D9S50.[ncbi.nlm.nih.gov]
  • arms and legs (short-limbed dwarfism ).[webmd.com]
  • arm of chromosome 9. [11] Immunodeficiency Patients with CHH usually suffer from cellular immunodeficiency.[wikiwand.com]
  • arm of chromosome 9. [11] Immunodeficiency [ edit ] Patients with CHH usually suffer from cellular immunodeficiency.[en.wikipedia.org]
  • And a little girl who would grow up to be four feet tall with exceedingly short arms and legs does not fit that paradigm. Seventeen years later, we are on the verge of being able to do something when our image of perfection is threatened.[theguardian.com]
Short Hands
  • Other symptoms include short hands and possibly short, deformed limbs (varus). X-ray reveals metaphyseal lesions, especially in the knees, and large, round epiphyses during childhood.[orpha.net]
  • Bowing of the lower extremities, a prominent reduction in the length of the tibia compared to the fibula, very short hands characterized by increased laxity of the metacarpal, interphalangeal and phalangeal joints, and incomplete extension of the elbow[symptoma.com]
  • 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[analesdepediatria.org]
Platyspondyly
  • […] chest with short ribs Conventional radiography short, bowed femurs with metaphyseal flare and irregularity eleven ribs , moderately short Flared and irregular metaphyses of multiple long bones are also associated with these dysplasias, as well as mild platyspondyly[radiopaedia.org]
  • .  Generalised severe platyspondyly  Increased intervertebral disc height  Open staircase vertebrae  Kyphosis/ scoliosis  Widening sclerosis irregularity of tubular bones  Irregular femoral epiphysis  Retarded bone maturation 17.[slideshare.net]
Short Extremities
  • It is a skeletal dysplasia characterized by short extremities, bowed legs, short and broad hands and feet, extreme ligamentous laxity and hypoplastic hair.[ctgt.net]
  • Before birth Possibly via prenatal ultrasound due to short extremities Genetic sampling if expected After birth X-ray findings Observation of common physical characteristics Confirmation by DNA testing of the RMRP gene via a blood test What are the common[littlepeopleuk.org]

Workup

CHH must be considered in the differential diagnosis of a short stature that appears from birth and accompanying features such as hair hypoplasia and immunodeficiency that predisposes individuals to recurrent infections. For this reason, a meticulously performed physical examination is a pivotal step. Despite the genetic nature of the disorder, its mode of inheritance (autosomal recessive) does not mandate a positive family history, but nevertheless, the appearance of similar signs and symptoms in close relatives or siblings must be noted. Laboratory studies will reveal transient macrocytic anemia, lymphopenia with a decreased CD4+/CD8+ T-cell count, and neutropenia [2] [3]. Imaging studies are used to distinguish CHH from numerous other causes of short stature. Metaphyseal dysplasia seen on X-rays of the limbs is the principal radiologic feature, accompanied by thickening and shortening of the tubular bones (distal femur, proximal tibia and bones of the hands), excessive length of the distal fibula, flaring of the costochondral junction, delayed ossification, and cone-shaped phalangeal epiphyses [3] [4]. If these features are identified during infancy, CHH is a highly likely diagnosis, in which case genetic studies should be pursued to confirm the underlying cause. Sequencing of the mitochondrial RNA-processing (RMRP) gene, the main culprit in the pathogenesis of CHH, located on chromosome 9p13.3 [1] [2], is available and advised whenever valid clinical suspicion exists based on clinical and radiographic criteria.

Anergy
  • A 29-year-old white woman had short limbs, hyperextendable joints, fine skin and body hair, anergy to common skin test antigens, subnormal lymphocyte response to phytohemagglutinin, and increased numbers of natural killer cells, characteristic of cartilage-hair[ncbi.nlm.nih.gov]
Sperm Count Decreased
  • Makitie et al. evaluated eleven adult CHH males (21-49 years), all patients had abnormal semen analysis characterized by low sperm count, decreased motility and morphological changes.[jpediatricsreview.com]
Lymphocytopenia
  • This could explain at least in part the severe lymphocytopenia in some patients with CHH and the observed low lymphocyte proliferation to specific mitogens in vitro.[bloodjournal.org]

Treatment

  • After the surgery, we continued GH treatment. Additional GH treatment of 3.6 more years had kept his height to -2.0 SD.[ncbi.nlm.nih.gov]
  • The rhGH treatment had a significant effect on the height gain: the height SD score was changed from -4. to -2.98 after 4 years 7 months of treatment. rhGH therapy should be considered as a treatment modality for CHH, and insulin-like growth factor (IGF[ncbi.nlm.nih.gov]
  • Serum immunoglobulins did not change during growth hormone treatment. We conclude that growth hormone treatment is not beneficial in children with CHH.[ncbi.nlm.nih.gov]
  • International experts analyse in detail the basic auxological characteristics of patients and their response to GH treatment for a broad spectrum of growth disorders.[books.google.com]

Prognosis

  • Prognosis The prognosis depends on the presence and severity of the immune deficiency and the possible association with Hirschsprung disease (see this term). The documents contained in this web site are presented for information purposes only.[orpha.net]
  • HD associated with CHH has poor prognosis in terms of postoperative morbidity and risk of death. These patients require particular attention during postoperative follow-up to detect potentially lethal complications.[ncbi.nlm.nih.gov]
  • Living with What is the prognosis for a person with Cartilage-Hair Hypoplasia? People with cartilage-hair hypoplasia can live a normal lifespan.[thinkgenetic.com]

Etiology

  • The etiology of this finding remains unclear. Some causes of such deposits can be of a reversible nature, thus prompting early recognition although their consequences on clinical outcome remain mostly unknown.[ncbi.nlm.nih.gov]
  • Cartilage-hair hypoplasia (CHH) is an autosomal recessive disease of unknown etiology characterized by metaphyseal dysostosis, unpigmented hair, and defective cellular immunity.[ncbi.nlm.nih.gov]
  • Etiology Mutations in the RMRP (RNA component of mitochondrial RNA-processing endoribonuclease) gene, which maps to the 9p21-p12 locus, are responsible for the disease.[orpha.net]

Epidemiology

  • An epidemiological and genetic study of CHH in Finland showed 107 patients, 46 males and 61 females, in 85 families. Eighteen of them had died, seven before the age of 1 year. The living patients ranged in age from 1 to 51 years, median 21 years.[ncbi.nlm.nih.gov]
  • One hundred twenty-two patients with CHH were identified through 2 countrywide epidemiologic surveys in 1974 and in 1986. Their parents and nonaffected siblings were identified through the Population Register Center.[ncbi.nlm.nih.gov]
  • Summary Epidemiology Prevalence is unknown. Clinical description The disease is associated with fine, slow growing hair, and sometimes with immune deficiencies. Other symptoms include short hands and possibly short, deformed limbs (varus).[orpha.net]
  • The discussion covers the phenotype spectrum, epidemiology, mode of inheritance, pathogenesis, and clinical profile of each condition, all of which is accompanied by a wealth of illustrations.[books.google.com]
Sex distribution
Age distribution

Pathophysiology

  • To report on the expanding clinical and immunological spectrum associated with ribonuclease mitochondrial RNA-processing mutations and to review the cellular and molecular mechanisms involved in the pathophysiology of cartilage-hair hypoplasia (CHH) and[ncbi.nlm.nih.gov]
  • Phalangeal cone-shaped epiphyses are an ideal object for the radiologist to study with temporal reasoning, to examine their shape, diagnostic usefulness, natural history and effect on pathophysiology.[ncbi.nlm.nih.gov]
  • Here, we critically review the underlying genetics in old and new ribosomopathies and examine the pathophysiologic consequences of aberrant ribosome biogenesis.[els.net]
  • Introduction Heterogeneous group of disorders characterized by metaphyseal changes of the tubular bones with normal epiphyses Epidemiology incidence skeletal dysplasias occur at a rate of 2 to 3 newborns per 10,000 births Pathophysiology metaphyseal dysplasia[orthobullets.com]
  • Pathophysiology The genetic defect in cartilage-hair hypoplasia has been identified as a mutation in the gene for RNAase RMRP, mapped to 9p12. [3, 4 , 5, 6 , 7, 8 , 9, 52 , 56] RMRP is a ribonucleoprotein present in the nucleus and mitochondria.[emedicine.medscape.com]

Prevention

  • In this patient, long-term administration of granulocyte colony-stimulating factor increased peripheral neutrophil counts and prevented recurrent hospitalizations for bacterial lower respiratory tract infections.[ncbi.nlm.nih.gov]
  • He also suggested regular doctor visits with preventative scans, to ensure that she lives for many years to come.[recapo.com]
  • […] after HSCT, whereas only rarely did they reach the age of 30 with best conventional treatment. 25 – 27 Hence, there is great hope that HSCT-associated restoration of normal T-lymphocyte and natural killer (NK)–cell immunity in CHH patients may also prevent[bloodjournal.org]
  • The goals of treatment are: to help children with CHH adapt socially and physically to prevent and treat any complications Various specialists work together as a team to help children with CHH.[aboutkidshealth.ca]
  • But when I looked for what Counsyl rather ominously calls "preventable genetic diseases" that are covered by its test, I immediately saw two forms of dwarfism.[theguardian.com]

References

Article

  1. Horn J, Schlesier M, Warnatz K, et al. Fatal adult-onset antibody deficiency syndrome in a patient with cartilage hair hypoplasia. Hum Immunol. 2010;71(9):916-919.
  2. Riley P, Weiner DS, Leighley B, et al. Cartilage hair hypoplasia: characteristics and orthopaedic manifestations. J Child Orthop. 2015;9(2):145-152.
  3. Baradaran-Heravi A, Thiel C, Rauch A, Zenker M, Boerkoel CF, Kaitila I. Clinical and Genetic Distinction of Schimke Immuno-Osseous Dysplasia and Cartilage-Hair Hypoplasia. American journal of medical genetics Part A. 2008;146A(15):2013-2017.
  4. Shiasi Arani K. Cartilage Hair Hypoplasia: First report from Iran. Med J Islam Repub Iran. 2013;27(3):157-160.

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