Cartilage-Hair Hypoplasia – Anauxetic Dysplasia Spectrum Disorders
Summary
Clinical characteristics.
The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes the following phenotypes:
- Metaphyseal dysplasia without hypotrichosis (MDWH)
- Cartilage-hair hypoplasia (CHH)
- Anauxetic dysplasia (AD)
CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature that is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility, fine silky hair, immunodeficiency, anemia, increased risk for malignancy, gastrointestinal dysfunction, and impaired spermatogenesis. The most severe phenotype, AD, has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn, and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family.
Diagnosis/testing.
Diagnosis of the CHH-AD spectrum disorders is based on clinical findings, characteristic radiographic findings, and in some cases, evidence of immune dysfunction, macrocytic anemia, and/or gastrointestinal problems. If clinical and radiographic findings are inconclusive, identification of biallelic pathogenic variants in RMRP by molecular genetic testing can confirm the diagnosis and allow for family studies.
Management.
Treatment of manifestations:
- In the newborn. Hypoplastic anemia may require repeated blood transfusions; congenital megacolon or Hirschsprung disease may require surgical resection.
- In childhood. Surgery may be needed to fuse unstable cervical vertebrae and/or to treat progressive kyphoscoliosis that compromises lung function in AD; corrective osteotomies may be required to treat progressive varus deformity associated with ligament laxity in the knees. Pubertal maturation may be delayed and may require hormonal induction.
- For those with immunodeficiency. Treatment of underlying infections based on their type, location, and severity; immediate antiviral treatment with intravenous high-dose acyclovir for varicella; consideration of prophylactic antibiotic therapy and/or immunoglobulin replacement therapy; physiotherapy and acute and long-term medical management for bronchiectasis. Recurrent severe infections and/or the presence of severe combined immunodeficiency (SCID) and/or severely depressed erythropoiesis may warrant bone marrow transplantation.
- Malignancies. Treat in the usual manner.
Prevention of secondary complications: If cervical spinal instability is identified in a person with AD, special care is required during general anesthesia.
Surveillance:
- Skeletal dysplasia. Clinical and (if warranted) radiographic monitoring of growth, joints of the lower extremities, and spine annually in childhood and as required in adulthood. Individuals with AD require annual clinical and radiographic monitoring of the spine.
- Anemia. For those who have not had anemia, observe for clinical signs of anemia; for those in remission after treatment, monitor for evidence of relapse.
- Immunodeficiency/infection. Monitor all children regardless of immune status during the first two years of life for recurrent infections, especially life-threatening varicella. Annual evaluation after age two years. High-resolution CT examination for those with features suggestive of bronchiectasis.
- Malignancies. No specific recommendations exist; regular examination for evidence of lymphomas, basal cell carcinomas, and other associated malignancies is advised.
- Endocrinology. Monitor pubertal maturation.
Agents/circumstances to avoid: Administration of live vaccines when signs of abnormal immunologic function or SCID are present.
Evaluation of relatives at risk: Early diagnosis of relatives at risk for the CHH-AD spectrum allows for early management of manifestations that can be associated with significant morbidity (e.g., infections, immunization with live vaccines, malignancies).
Genetic counseling.
The CHH-AD spectrum is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier of a pathogenic variant, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.
Diagnosis
There are no formal diagnostic criteria for CHH, as individuals present with highly variable phenotypes.
The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum ranging from short stature without hypotrichosis with only radiographic evidence of metaphyseal dysplasia (MDWH) [Bonafé et al 2002] to short stature with hypotrichosis and variable metaphyseal dysplasia of the tubular bones (CHH) [McKusick et al 1965, Mäkitie & Kaitila 1993] to severe deforming short stature with metaphyseal, epiphyseal, and vertebral dysplasia (anauxetic dysplasia [AD]) [Horn et al 2001, Thiel et al 2005].
Newborn screening for severe combined immunodeficiency using detection of T-cell receptor excision circles is able to identify some of the individuals with CHH prior to recognition of other findings [Kwan et al 2013].
Suggestive Findings
CHH-AD spectrum disorders should be suspected in individuals with:
- Mild to severe disproportionate short-limbed short stature (final adult height <85-151 cm)
- Presence of variable metaphyseal dysplasia with epiphyseal and vertebral dysplasia in the severe end of the spectrum
Especially when accompanied by:
- Short tubular bones
- Bowed femora and tibiae
- "Bullet"-shaped middle phalanges, cone-shaped epiphyses, and premature epiphyseal fusion on hand radiographs
- Laxity of ligaments with joint hypermobility, but limited extension of the elbows
- Fine, silky hair
- Increased rate of infections or intestinal dysfunction or anemia
Clinical Findings by Phenotype
Cartilage-hair hypoplasia (CHH)
- Disproportionate short-limb short stature (present in 100% of affected adults; prenatal onset in 76%-93%)
- Short fingers and toes
- Bowed femora and tibiae (present in 77%)
- Laxity of ligaments with hypermobility of joints (87%)
- Limited extension of the elbows (83%)
- Lumbar lordosis, chest deformity (~50%)
- Blonde, sparse, fine silky hair (89%-93%)
- Impaired lymphocyte proliferation and T-lymphocyte function (88%) with increased rate of:
- Infections in infancy and childhood (35%-65%)
- Severe varicella infection (11%)
- Severe combined immunodeficiency
- Bronchiectasis (29%) [Kostjukovits et al 2017a]
- Macrocytic, hypoplastic anemia in early childhood (79%)
- Lymphomas; leukemia; neoplasms of the skin, eye, and liver (6%-11%)
- Congenital megacolon or Hirschsprung disease (7%-8%)
- Intestinal malabsorption with diarrhea and failure to thrive
- Cutaneous and visceral granulomas [Moshous et al 2011, McCann et al 2014]
Metaphyseal dysplasia without hypotrichosis (MDWH)
- Clinical features similar to CHH, but with normal hair
- Absence of immunodeficiency, anemia, and intestinal manifestations
Anauxetic dysplasia (AD)
- Prenatal onset of extreme short-limb short stature (100%)
- Barrel chest with hyperlordosis and kyphoscoliosis
- Dislocated hips
- Atlantoaxial subluxation leading to cervical spine compression
- Facial features. Midfacial hypoplasia and macroglossia
- Dental abnormalities
- Mild intellectual disability
Radiographic Findings by Phenotype
Note: Radiographic findings tend to be highly variable.
Cartilage-hair hypoplasia (CHH)
- Short and thick tubular bones
- Short and bullet-shaped metacarpals and phalanges with cone-shaped epiphyses
- Metaphyseal dysplasia of all tubular bones, most prominent changes at the knees
- Distal metaphyses. Wide, flared, occasionally scalloped with cystic areas; poor ossification with trabeculation
- Epiphyseal changes. Absent or mild in the femoral head
- Vertebral bodies. Normal or mild biconvexity with increased height, lumbar lordosis, reduced widening of interpediculate distance in the lumbar spine
Metaphyseal dysplasia without hypotrichosis (MDWH). Similar to those in CHH
Anauxetic dysplasia (AD)
- Vertebral bodies. Late-maturing ovoid with concave dorsal surfaces in the lumbar region; dislocation in the cervical spine
- Femora. Small capital femoral epiphyses with hypoplastic femoral necks
- Iliac bodies. Hypoplastic
- Acetabulae. Shallow
- Metacarpals. Short with widened shafts (I and V)
- Phalanges. Very short and broad with small, late ossifying epiphyses and bullet-shaped middle phalanges
Establishing the Diagnosis
The diagnosis of CHH-AD is established in a proband with the above Suggestive Findings including clinical and characteristic radiographic findings. If clinical and radiographic findings are inconclusive, identification of biallelic pathogenic variants in RMRP by molecular genetic testing (see Table 1) can confirm the diagnosis and allow for family studies.
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CHH-AD is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other inherited disorders with short stature and/or immune deficiency are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of CHH-AD molecular genetic testing approaches can include single-gene testing or use of a multigene panel:
- Single-gene testing. Sequence analysis of RMRP detects nucleotide variants and small intragenic deletions/insertions/duplications; typically, heterozygous whole-gene deletions/duplications are not detected. Perform sequence analysis first. Sequence analysis should cover both the transcribed region and the promoter region. If only one or no pathogenic variant is found perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.Targeted analysis for the common g.70A>G pathogenic variant can be performed first in individuals of Finnish or Amish ancestry.Note: This noncoding RNA spans only 268 bp; therefore, targeted testing by sequence analysis is likely to result in analysis of the entire gene.
- A multigene panel that includes RMRP and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by short stature, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used, but genome sequencing is also possible; however, regardless of the method, RMRP pathogenic variants may not be detected because RMRP is a small (268-bp) untranslated gene without introns and exons. Note that although exome sequencing is defined traditionally as the sequence encompassing all exons of protein-coding genes in the genome it also may be extended to target functional non-protein-coding elements such as RMRP.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in CHH-AD Spectrum Disorders
| Gene 1 | Method | Proportion of Pathogenic Variants 2 Detectable by Method |
|---|---|---|
| RMRP | Sequence analysis 3 | ~100% 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include nucleotide substitution and small intragenic deletions. Typically, whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Martin & Li [2007]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
To date, no large deletions or duplications involving RMRP have been reported to cause CHH-AD spectrum disorders [Ridanpää et al 2001, Thiel & Rauch 2011].
Clinical Characteristics
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]:
- Atlantoaxial subluxation with fatal cervical compression
- Mild intellectual disability
Genotype-Phenotype Correlations
The CHH-AD spectrum includes a range of phenotypes. RMRP is not translated into a protein; thus, genotype-phenotype correlation depends on the position of the pathogenic variant in the transcript and the proposed effect on transcript folding and RNA/protein interaction (see Molecular Genetics).
The milder phenotypes are usually caused by either of the following:
- Compound heterozygous or homozygous pathogenic variants within the transcript resulting in little to intermediate effect on function of the RNase MRP (complex formed of the RMRP transcript and other proteins)
- Compound heterozygosity for one pathogenic variant within the transcript and one pathogenic variant in the promoter region
AD is caused by either of the following:
- Compound heterozygous or homozygous biallelic pathogenic variants that severely alter function OR
- Compound heterozygosity for:
- One pathogenic variant within the transcript that severely alters the RNase MRP function AND
- A hypomorphic (reduced function) allele (e.g., pathogenic variant leading to an unstable transcript)
Nomenclature
Cartilage hair hypoplasia (CHH) or metaphyseal chondrodysplasia, McKusick type was first described in the Old Order Amish population by McKusick and his colleagues [McKusick et al 1965].
Individuals with normal hair and metaphyseal dysplasia, called metaphyseal dysplasia without hypotrichosis (MDWH), were reported by Bonafé et al [2002].
Anauxetic dysplasia was named after the Greek "not to permit growth" [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].
Differential Diagnosis
Table 2.
Disorders to Consider in the Differential Diagnosis of Cartilage-Hair Hypoplasia – Anauxetic Dysplasia (CHH-AD) Spectrum Disorders
| Differential Diagnosis Disorder | Gene(s) | MOI | Clinical Features | |
|---|---|---|---|---|
| Overlapping | Distinguishing | |||
| Anauxetic dysplasia 2 (OMIM 617396) | POP1 | AR |
| In anauxetic dysplasia 2: no clinical symptoms of immunodeficiency |
| Anauxetic dysplasia 3 (OMIM 618853) | NEPRO | AR |
| In anauxetic dysplasia 3: no clinical symptoms or laboratory signs of immunodeficiency |
| Schmid dysplasia | COL10A1 | AD | Short stature & radiographic metaphyseal abnormalities (metaphyseal dysplasia especially in proximal femur) resembling CHH | In Schmid dysplasia: no extraskeletal manifestations |
| Jansen dysplasia (OMIM 156400) | PTH1R | AD | Short stature & radiographic metaphyseal abnormalities resembling CHH | In Jansen dysplasia: hypercalcemia & hypercalciuria 3 |
| Shwachman-Diamond syndrome (SDS) | SBDS | AR |
| In SDS:
|
| Schimke immunoosseous dysplasia (SIOD) | SMARCAL1 | AR |
| In SIOD:
|
| Combined immunodeficiency syndromes | See footnote 6. | AD AR XL | Immunodeficiency | In most immunodeficiency syndromes: no skeletal abnormalities |
| Omenn syndrome (OMIM 603554) | RAG1 RAG2 DCLRE1C | AR |
| Omenn syndrome is more severe & incls:
|
| Isolated congenital neutropenia (See ELANE-Related Neutropenia.) | See footnote 8. | AD AR XL | Congenital neutropenia | Skeletal phenotype in CHH |
| Syndromic congenital neutropenia 7 (See WAS-Related Disorders, G6PC3 Deficiency.) | ||||
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
- 1.
Glazov et al [2011]
- 2.
Narayanan et al [2019]
- 3.
Savoldi et al [2013]
- 4.
Levin et al [2015]
- 5.
If recurrent infections are present, milder forms of SIOD may be confused with CHH [Baradaran-Heravi et al 2008].
- 6.
See OMIM Phenotypic series: Immunodeficiency (Select Examples) - PS300755 for genes associated with this phenotype in OMIM.
- 7.
Congenital neutropenia that occurs as part of a syndrome can be caused by pathogenic variants affecting glucose metabolism or lysosomal function.
- 8.
See OMIM Phenotypic series: Neutropenia, severe congenital - PS202700 for genes associated with this phenotype in OMIM.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with a cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorder, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with CHH-AD Spectrum Disorder
| System/Concern | Evaluation | Comment |
|---|---|---|
| Respiratory | Pulmonary consultation | Eval for evidence of respiratory disease |
| Gastrointestinal/ Feeding | Gastroenterologic consultation | Eval for congenital megacolon if clinical observation is suggestive |
| Musculoskeletal | Full skeletal survey | To incl (in AD) views of cervical spine to identify cervical vertebral abnormalities & assess risk for atlantoaxial subluxation |
| Orthopedic consultation | Eval for complications of joint laxity, lumbar lordosis, chest deformity, scoliosis, & varus deformity of lower extremities | |
| Hematologic/ Lymphatic | Complete blood count w/differential cell count | Eval for macrocytic anemia & immunodeficiency 1 |
| Hematologic consultation | If blood count is abnormal, for further assessment & treatment | |
| Allergic/ Immunologic | Laboratory evals for immunodeficiency 1 | To incl:
|
| Immunologic consultation | If immunologic testing is abnormal or if child has infections, for assessment & treatment & to determine vaccination program & approach to varicella prophylaxis | |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor |
AD = anauxetic dysplasia; TREC = T-cell receptor excision circles
- 1.
Rider et al [2009]
Treatment of Manifestations
Skeletal dysplasia
- Corrective osteotomies may be warranted in late childhood or adolescence for excessive varus deformity of the lower extremities [Riley et al 2015].
- In persons with AD, surgery may be needed to fuse malformed cervical vertebrae in infancy and to correct or prevent the progression of kyphoscoliosis.
- Orthopedic surgery may be complicated by low bone density.
Short stature. Treatment with recombinant growth hormone has not shown any sustained benefit in individuals with CHH and cannot be recommended [Obara-Moszynska et al 2013].
Immunodeficiency and infection. The treatment of infections in individuals with immunodeficiency is based on their type, location, and severity.
- Immediate antiviral treatment with intravenous high-dose acyclovir must be considered at the first symptoms of varicella infection to prevent complications.
- Consider prophylactic antibiotic therapy if the individual has recurrent infections or if neutropenia/severe lymphopenia is present. Consider also immunoglobulin replacement therapy if immunoglobulin or IgG subclass levels are low, or if vaccine responses are inadequate.
- Individuals with bronchiectasis need proper management of infectious exacerbations