Increased incidence of cancer in patients with cartilage-hair hypoplasia

doi:10.1016/S0022-3476(99)70456-7

The Journal of Pediatrics

Volume 134, Issue 3, March 1999, Pages 315-318

https://doi.org/10.1016/S0022-3476(99)70456-7 Get rights and content

Abstract

Objective: Previous reports have suggested an increased risk of cancer among patients with cartilage-hair hypoplasia (CHH). This study was carried out to further evaluate this risk among patients with CHH and their first-degree relatives. Study design: 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. This cohort underwent follow-up for cancer incidence through the Finnish Cancer Registry to the end of 1995. Results: A statistically significant excess risk of cancer was seen among the patients with CHH (standardized incidence ratio 6.9, 95% confidence interval 2.3 to 16), which was mainly attributable to non-Hodgkin’s lymphoma (standardized incidence ratio 90, 95% confidence interval 18 to 264). In addition, a significant excess risk of basal cell carcinoma was seen (standardized incidence ratio 35, 95% confidence interval 7.2 to 102). The cancer incidence among the siblings or the parents did not differ from the average cancer incidence in the Finnish population. Conclusions: This study confirms an increased risk of cancer, especially non-Hodgkin’s lymphoma, probably attributable to defective immunity, among patients with CHH. (J Pediatr 1999;134:315-8)

Section snippets

METHODS

Patients with CHH were identified through 2 thorough epidemiologic surveys carried out in Finland in 1974¹¹ and in 1986.¹ Since 1986 we have received information on all patients with CHH diagnosed in Finland. The diagnosis of CHH was based on short-limbed short stature, generalized laxity of joint ligaments, generalized metaphyseal flaring and irregularities in childhood radiographs, and genealogy compatible with autosomal recessive inheritance.2, 3 Hair hypoplasia was used only as a positive

Patients with CHH

A total of 51 men and 71 women were included in the CHH cohort (probands and affected siblings combined). The numbers of person-years were 658 and 751, respectively (Table I).

. Number of patients with CHH under follow-up and number of person-years at risk in 1967 to 1995 by age and sex

Age	Male subjects		Female subjects
Age	N	Person-years	N	Person-years
<15 years	41	261	51	287
15-29 years	8	270	8	266
30-44 years	1	116	7	146
45+ years	1	11	5	52
Total	51	658	71	751

The mean length of follow-up of a person was thus 11.5 years. During

DISCUSSION

The main clinical characteristics of CHH were originally outlined in a study of 77 patients among the Old Order Amish, a religious isolate in the United States.² The association of CHH and defective immunity was suspected because of severe attacks of varicella among these patients.² In subsequent studies the deficiency of cell-mediated immunity was confirmed,4, 13 and some cases of cancer were reported.3, 6, 7, 8

The present countrywide cohort of Finnish patients with CHH (122) is the largest

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Specific inherited immune deficiency syndromes—such as ataxia telangiectasia (ATM), Bloom syndrome (BLM), Wiskott Aldrich syndrome (WAS), Nijmegen Breakage syndrome (NBS1), cartilage hair hypoplasia (RMRP), adenosine deaminase 1 deficiency (ADA1), Bruton agammaglobulinemia (BTK), and many others—are also associated with an increased risk of B- and T-cell lymphomas.62 Cartilage hair hypoplasia is especially unique as it has some degree of phenotypic overlap with dyskeratosis congenita (DKC), is associated with critically shortened lymphocyte telomere length secondary to a perturbed telomere homeostasis, significant immunodeficiency and predisposition to lymphoid neoplasms.129,130 Among B-cell lymphomas in patients with primary immunodeficiency and immune dysregulatory disorders, a meta-analysis has shown a frequency of 37% for unspecified NHL, 15% for diffuse large B-cell lymphoma, 13% for HL, 5% for HL and marginal zone lymphoma, 4% for Burkitt lymphoma, and 0.4% for diffuse histiocytic lymphoma, respectively.62
With the advent of precision genomics, hereditary predisposition to hematopoietic neoplasms— collectively known as hereditary predisposition syndromes (HPS)—are being increasingly recognized in clinical practice. Familial clustering was first observed in patients with leukemia, which led to the identification of several germline variants, such as RUNX1, CEBPA, GATA2, ANKRD26, DDX41, and ETV6, among others, now established as HPS, with tendency to develop myeloid neoplasms. However, evidence for hereditary predisposition is also apparent in lymphoid and plasma--cell neoplasms, with recent discoveries of germline variants in genes such as IKZF1, SH2B3, PAX5 (familial acute lymphoblastic leukemia), and KDM1A/LSD1 (familial multiple myeloma). Specific inherited bone marrow failure syndromes—such as GATA2 haploinsufficiency syndromes, short telomere syndromes, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, severe congenital neutropenia, and familial thrombocytopenias—also have an increased predisposition to develop myeloid neoplasms, whereas inherited immune deficiency syndromes, such as ataxia-telangiectasia, Bloom syndrome, Wiskott Aldrich syndrome, and Bruton agammaglobulinemia, are associated with an increased risk for lymphoid neoplasms. Timely recognition of HPS is critical to ensure safe choice of donors and/or conditioning-regimen intensity for allogeneic hematopoietic stem-cell transplantation and to enable direction of appropriate genomics-driven personalized therapies. The purpose of this review is to provide a comprehensive overview of HPS and serve as a useful reference for clinicians to recognize relevant signs and symptoms among patients to enable timely screening and referrals to pursue germline assessment. In addition, we also discuss our institutional approach toward identification of HPS and offer a stepwise diagnostic and management algorithm.
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Patients display short stature, hypoplastic hair, and variable degree of defective cell mediated and humoral immunity. Individuals with cartilage-hair hypoplasia have 5–7 higher risk for malignancy, particularly EBV-driven lymphoproliferative disease and lymphoma [100]; [101]; [102]; [103]. There is also a high incidence of NHL, as well as documented cases of leukemia and HL [103].
Primary Immunodeficiency disorders (PID) have been increasingly recognized in association with hematologic malignancies. To better appreciate this association, a systemic search of the Ovid MEDLINE database was performed with terms related of hematologic malignancies and all PID described in the 2017 International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. More than 60 PID distinct PID, caused by cell-intrinsic and extrinsic mechanisms were associated with diverse hematologic malignancies. These occurred among all subgroups of PID, including syndromic and non-syndromic combined PID affecting cellular and humoral immunity, predominantly antibody deficiencies and defects of immune regulation. In addition, defects in phagocyte numbers or functions, or in innate immunity were associated with hematologic malignancies. Increased awareness and vigilance for the possibility of malignancy is required when caring for patients with PID.
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Defects in lymphocyte telomere homeostasis contribute to cellular immune phenotype in patients with cartilage-hair hypoplasia
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Mutations in the long noncoding RNA RNase component of the mitochondrial RNA processing endoribonuclease (RMRP) give rise to the autosomal recessive condition cartilage-hair hypoplasia (CHH). The CHH disease phenotype has some overlap with dyskeratosis congenita, a well-known “telomere disorder.” RMRP binds the telomerase reverse transcriptase (catalytic subunit) in some cell lines, raising the possibility that RMRP might play a role in telomere biology.
We sought to determine whether a telomere phenotype is present in immune cells from patients with CHH and explore mechanisms underlying these observations.
We assessed proliferative capacity and telomere length using flow–fluorescence in situ hybridization (in situ hybridization and flow cytometry) of primary lymphocytes from patients with CHH, carrier relatives, and control subjects. The role of telomerase holoenzyme components in gene expression and activity were assessed by using quantitative PCR and the telomere repeat amplification protocol from PBMCs and enriched lymphocyte cultures.
Lymphocyte cultures from patients with CHH display growth defects in vitro, which is consistent with an immune deficiency cellular phenotype. Here we show that telomere length and telomerase activity are impaired in primary lymphocyte subsets from patients with CHH. Notably, telomerase activity is affected in a gene dose-dependent manner when comparing heterozygote RMRP carriers with patients with CHH. Telomerase deficiency in patients with CHH is not mediated by abnormal telomerase gene transcript levels relative to those of endogenous genes.
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^☆: Supported by a grant from the Ulla Hjelt Foundation, Helsinki, Finland.

^☆☆: Reprint requests: Outi Mäkitie, MD, Hospital for Children and Adolescents, Helsinki University Hospital, Stenbäckinkatu 11, FIN-00290 Helsinki, Finland.

^★: 0022-3476/99/$8.00 + 0 9/22/96110

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Increased incidence of cancer in patients with cartilage-hair hypoplasia☆,☆☆,★

Abstract

Section snippets

METHODS

Patients with CHH

DISCUSSION

Clin Immunol Immunopath

J Pediatrics

Cartilage-hair hypoplasia in Finland: epidemiological and genetic aspects of 107 patients

J Med Genet

Dwarfism in the Amish II. Cartilage-hair hypoplasia

Bull Johns Hopkins Hosp

Cartilage-hair hypoplasia: clinical manifestations in 108 Finnish patients

Eur J Pediatr

Cellular and humoral immunity in cartilage-hair hypoplasia

Pediatr Res

Cartilage-hair hypoplasia gene assigned to chromosome 9 by linkage analysis

Nature Genet

Cartilage-hair hypoplasia in the Amish: increased susceptibility to malignancy [abstract]

Am J Hum Genet

Cartilage-hair hypoplasia, defective T-cell function, and Diamond-Blackfan anemia in an Amish child

Am J Med Genet

McKusick’s dwarfism and resistant Hodgkin’s disease [letter]

J Am Osteopath Ass