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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
  • Imaging studies are used to distinguish CHH from numerous other causes of short stature.[symptoma.com]
  • Context&58; Cartilage-hair hypoplasia is a rare hereditary cause of short stature. The aim of this study was to familiarize physicians with this rare but important disease.[ingentaconnect.com]
  • It has since been found in many other populations and is the most common form of short stature among Amish settlements. The hallmarks are short stature and thin, sparse, and light-colored hair. [wohproject.org]
  • stature of varying origin.[books.google.com]
  • Cartilage-hair hypoplasia (say: hie-po-PLAY-zee-a), or CHH, is a genetic condition that results in: short stature (height) shorter arms and legs than expected fine, sparse hair anemia, a low number of red blood cells problems with the immune system Another[aboutkidshealth.ca]
Anemia
  • We did not observe an anemia phenotype.[dukespace.lib.duke.edu]
  • In 11 patients, anemia developed before five months of age; one patient developed aplastic anemia at 2.5 years of age, 10 patients had normocytic anemia, but two had macrocytic anemia, five patients had thrombocytosis.[jpediatricsreview.com]
  • 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]
  • All patients have disproportionately short limbs and stature, and most present with skeletal deformities, joint hypermobility, autoimmune deficiency, and anemia.[sema4genomics.com]
  • In early childhood, most people with CHH have severe anemia because they have low levels of red blood cells. Symptoms of anemia include paler skin and decreased energy. Gastrointestinal problems Some people with CHH have gastrointestinal problems.[aboutkidshealth.ca]
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]
  • A third of affected individuals (32 per cent) have severe or recurrent infections and several (8 per cent) have required bone marrow transplants for combined immunodeficiency.[wohproject.org]
  • Nearly 56% of younger children experience recurrent infections, especially respiratory tract infections. Children are unusually susceptible to chicken pox. In McKusick’s original study, 6 patients died due to fatal varicella pneumonia.[nemours.org]
  • The onset of increased susceptibility to recurrent infections and severity of infections is somewhat more variable in cartilage-hair hypoplasia.[emedicine.medscape.com]
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]
  • 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]
  • 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]
Sparse Hair
  • The name “Cartilage Hair Hypoplasia” was coined due to the characteristic features: fine, sparse hair and cartilage abnormalities.[nemours.org]
  • Cartilage-hair hypoplasia (say: hie-po-PLAY-zee-a), or CHH, is a genetic condition that results in: short stature (height) shorter arms and legs than expected fine, sparse hair anemia, a low number of red blood cells problems with the immune system Another[aboutkidshealth.ca]
  • Individuals with cartilage hair hypoplasia have: Light, fine, sparse hair Loose ligaments in the elbows, causing instability Bowing of their legs (genu varum) Possible neck instability Risk of infections due to a change in immunity (which is protection[hopkinsmedicine.org]
  • The symptoms of Cartilage-Hair Hypoplasia are: immune deficiency, fine/sparse hair, and short stature along with other skeletal abnormalities, light-colored hair and light-colored skin.[pingrybiology.pbworks.com]
  • Treatment: There is no known treatment for the short stature and sparse hair. Conventional medical and surgical treatment for aganglionosis and malignancies should be used.[wohproject.org]
Skin Lesion
  • 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.[link.springer.com]
  • Lumbar lordosis is increased ( 11 ).[jpediatricsreview.com]
  • . - Orthopedic problems: The lumbar lordosis and ligamentous laxity can cause joint pains of the lower spine, the knees and ankles. - Immunodeficiency: The cellular immunity may be defective whereas the humoral immunity is usually intact.[atlasgeneticsoncology.org]
  • […] 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 stenosis & excessive lordosis with spinal cord / nerve root compression  Radial head subluxation  Normal intelligence but delayed motor milestones 10.[slideshare.net]
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]
Short Arm
  • 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]
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.

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]
Macrocytosis
  • Mäkitie O, Rajantie J, Kaitila I (1992) Anemia and macrocytosis, unrecognized features of cartilage-hair hypoplasia. Acta Paediatr (in press) Google Scholar 19.[link.springer.com]
  • Macrocytosis may be seen without anemia. The reticulocyte index was low considering the hemoglobin value ( 11 ). Routine bone marrow examination is not recommended.[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

  • 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]
  • Not everyone with CHH has the same symptoms or requires the same treatments.[thinkgenetic.com]
  • Cartilage Hair Hypoplasia Treatment There are multiple treatment options for the symptoms of cartilage hair hypoplasia based on the area and severity of the condition.[hopkinsmedicine.org]
  • Treatment: There is no known treatment for the short stature and sparse hair. Conventional medical and surgical treatment for aganglionosis and malignancies should be used.[wohproject.org]

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]
  • 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]
  • […] loose jointed) Cartilage deformities on long bones (e.g. arms, legs) Sparse, fine, light-colored hair Very fair skin Immunologic deficiencies Frequent infections Anemia Increased risk cancer of the skin, blood, or immune system Cartilage Hair Hypoplasia Prognosis[evolvegene.com]

Etiology

  • 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]
  • The etiology of this complication could be related to RMRP -associated cell-cycle regulation, but viral infections should also be a factor. In all such cases, this HSCT successfully restored bone marrow function and cellularity.[bloodjournal.org]

Epidemiology

  • 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]
  • Materials and methods Patients with CHH were identified through two thorough epidemiological surveys carried out in Finland in 1974 8 and in 1986. 9 Since 1986 we have received information on all CHH patients diagnosed in Finland; they were also included[adc.bmj.com]
Sex distribution
Age distribution

Pathophysiology

  • 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]
  • 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]

Prevention

  • 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]
  • Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir. Bone Marrow Transplant . Mar 2000. 25(6):657-64. [Medline] . Thiel CT.[emedicine.medscape.com]
  • 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.

Symptoms

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