Clinical Description
Cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes three phenotypes:
Metaphyseal dysplasia without hypotrichosis (MDWH);
Cartilage-hair hypoplasia (CHH), with metaphyseal dysplasia and hypotrichosis; and
At the severe end, the rare anauxetic dysplasia (AD), with the most pronounced skeletal
phenotype.
The mechanisms for phenotypic variability are incompletely understood (see Genotype-Phenotype Correlations).
Disproportionate short-limb short stature is the hallmark finding and is usually recognized in the newborn and occasionally prenatally. Proportionate short stature has been observed in some individuals [van der Burgt et al 1991, Mäkitie & Kaitila 1993]. Normal growth in childhood has also been reported [Klemetti et al 2017]. Growth failure is progressive and associated with the degree of disproportion. Lumbar lordosis and scoliosis may contribute to the short stature.
Marked inter- and intrafamilial variability of short stature has been observed. Growth curves for Finnish individuals with CHH have been published. Final adult height ranges from 104 to 151 cm in CHH (median: 131 cm in males; 122 cm in females) and less than 85 cm in AD [Mäkitie et al 1992a, Mäkitie & Kaitila 1993, Horn et al 2001].
Laxity of ligaments with joint hypermobility is marked especially in the hands and feet. The laxity of lateral ligaments of the knees contributes to the varus deformity of the lower extremities.
Fine silky hair. Sparse hair, reduction of the diameter of the hair shaft, and loss of the central pigmented core of the hair shaft contribute to the distinctive appearance of the hair. About 15% of affected persons have complete primary alopecia including scalp hair and eyelashes, eyebrows, and body hair.
Immunodeficiency may manifest as lymphopenia and defects in T-lymphocyte function and/or proliferation [Kavadas et al 2008]. Sometimes defects in B-lymphocyte proliferation with low IgG and undetectable IgA are observed. Although deficient cellular immunity is present in most affected individuals (88%), an increased rate of infection is noted in only 35%-65%, usually during infancy and childhood. Early reports on fatal varicella infection conflict with the more recent publications on larger cohorts of individuals with CHH with mostly uncomplicated varicella disease [Mäkitie et al 1998]. Severe respiratory disease (e.g., lymphoplasmacytic bronchiolitis) has been reported in children [Bailly-Botuha et al 2008]. Chronic viral infections with bocavirus and norovirus have been reported [Kainulainen et al 2014]. Impaired cellular immunity persists into adulthood. Individuals with CHH and combined immunodeficiency are at particular risk for chronic bronchiectasis [Toiviainen-Salo et al 2008], which may, however, develop even in individuals with mild immunodeficiency [Kostjukovits et al 2017a]. Fatal enteroviral meningoencephalitis has been reported in a child with CHH [Vatanavicharn et al 2010].
Autoimmune complications. In rare instances autoimmune complications and a form of severe allergic reaction have been observed in CHH; however, the pathophysiology is still unknown [Bacchetta et al 2009, Narra & Shearer 2009]. Cutaneous and visceral granulomatous inflammatory lesions have been described in five individuals with CHH [Moshous et al 2011, McCann et al 2014]. Individuals with CHH demonstrate broad autoantibody reactivity compared to healthy controls [Biggs et al 2017].
Anemia. Deficient erythropoiesis may lead to mild to severe macrocytic anemia. Mild anemia is seen in about 80% of those with CHH and resolves spontaneously in childhood in most cases [Mäkitie et al 1992b]. Severe and persistent anemia resembling that of Diamond-Blackfan syndrome is seen in about 6% [Williams et al 2005]. About 50%-75% of those with severe anemia require lifelong transfusions or bone marrow transplantation (see Management); on occasion spontaneous resolution is observed [Williams et al 2005].
Malignancies. Extended follow up of persons with CHH revealed that about 11% of the cohort (14/123) followed for 39 years had developed malignancies [Taskinen et al 2008]. Kaplan-Meier estimate gave a probability of a cancer event (excluding basal cell carcinoma) of 41% by age 65 years.
Nine of the 14 malignancies were diagnosed in persons age 15-44 years. Of the 14 who developed malignancies, nine have died; median time to death was three months after initial diagnosis of the malignancy. Underlying pathogenic variants in RMRP and severity of preceding immunodeficiency varied and did not correlate with risk of malignancy.
The most frequently observed cancers are non-Hodgkin lymphoma, followed by squamous cell carcinoma, leukemia, and Hodgkin lymphoma; non-aggressive basal cell carcinoma was also common. There are isolated reports of uterine carcinoma and vocal cord carcinoma [Kostjukovits et al 2017b]. Rarely, two or more malignancies are observed in one individual.
Intestinal problems
Newborn period. Hirschsprung disease with short-segment or total colon aganglionosis is observed in 7%-8% of those with CHH, especially infants with the severe forms of CHH [
Mäkitie et al 2001a].
Infancy. When Hirschsprung disease has been excluded, malabsorption secondary to gastrointestinal infections can occur in the first two years of life [
Mäkitie et al 1995]. The main findings are "celiac syndrome" with diarrhea and failure to thrive. Although most intestinal manifestations occur in the first two years of life, they can occur later in childhood. Intestinal problems have not been described in AD or MDWH.
Impaired spermatogenesis. Because of a defect in cell proliferation, males with CHH have defects in sperm concentration, motility, morphology, and immunology [Mäkitie et al 2001b]. Testicles are smaller than normal for age and pubertal status; however, serum concentrations of testosterone, inhibin B, and gonadotropins are within the normal range in most individuals.
Delayed puberty. Girls with CHH may have hypogonadotropic or normogonadotropic hypogonadism with no spontaneous pubertal development [Holopainen et al 2018].
Additional findings observed in some persons with AD [Horn et al 2001]:
Prevalence
About 700 individuals are currently known to have a CHH-AD spectrum disorder [Kaitila, personal communication]. The most severe form, AD, is extremely rare: fewer than ten affected individuals have been reported.
Affected individuals have been reported in most populations; however, a high incidence of CHH was noted in the Old Order Amish population with a prevalence of 1:1,000-2:1,000 (carrier frequency 1:10) and in Finland with an incidence of 1:23,000 (carrier frequency 1:76) [Mäkitie 1992, Mäkitie & Kaitila 1993].