RESUMEN
Silver Russell syndrome (SRS) is a congenital disorder characterized by intrauterine growth retardation (IUGR), feeding difficulties and postnatal growth retardation. In a small number of cases, PLAG1 variants have been described (OMIM #618907). PLAG1 haploinsufficiency decreases Insulin-like growth factor 2 expression and produces a Silver Russell syndrome-like phenotype. Here, we describe the phenotype and molecular features of a 26 months girl with clinical features of SRS, and a de novo 2.1 Mb deletion encompassing PLAG1 is reported in association with clinical features suggestive of SRS.
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Síndrome de Silver-Russell , Proteínas de Unión al ADN/genética , Femenino , Humanos , Fenotipo , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética , Factores de Transcripción/genéticaRESUMEN
INTRODUCTION: Russell-Silver syndrome (RSS) is a unique cause of syndromic, and often severe, limb length discrepancy (LLD). RSS causes growth retardation both in utero and postnatally, with asymmetry in limb length more noticeable as growth progresses throughout childhood and adolescent. We aim to present the largest cohort in the literature on limb lengthening in patients with RSS and to validate previous literature supporting faster bony consolidation in these patients with more robust data. We further aim to establish differences in healing within this cohort based on age, sex, segment lengthened, or type of lengthening procedure performed, to help refine patient expectations and guide practitioners in treating this population. METHODS: This was a retrospective study of patients with a diagnosis of RSS who underwent a limb lengthening procedure for the purpose of limb equalization. They were compared with a historic control group of patients who underwent limb lengthening for LLD of a non-RSS etiology. The primary outcome measure was bone healing index (BHI). RESULTS: The RSS group consisted of 24 patients with 29 segments lengthened, and was compared with a historic control group consisting of 20 patients with 22 segments lengthened (Goldman). Patients with RSS had a significantly lower BHI, and therefore faster healing of their lengthening site, than their non-RSS peers (P=0.02). Within the RSS cohort, we did not detect a difference in BHI based on intervention type or sex, but we did find a trend toward faster healing in femurs over tibiae (P=0.08), and established that younger patients tended toward lower BHIs (P<0.01). CONCLUSIONS: Our results confirmed with more robust data the prior finding that patients with RSS may undergo limb lengthening procedures at least as safely as their non-RSS counterparts, and with even faster bony consolidation, especially in younger patients. We hypothesize that concurrent treatment with growth hormone supplementation may contribute to this finding, although further study is necessary. This is the largest cohort of RSS patients treated with limb lengthening for LLD reported in the literature, and these findings will help to guide surgeon decision-making when treating this unique population. LEVEL OF EVIDENCE: Level III-retrospective comparative study.
RESUMEN
Imprinting disorders (IDs) often affect growth in humans, leading to diseases with overlapping features, regardless of the genomic region affected. IDs related to hypomethylation of the human 14q32.2 region and its DLK1/MEG3 domain are associated with Temple syndrome (TS14). TS14 is a rare type of growth retardation, the clinical signs of which overlap considerably with those of Silver-Russell syndrome (SRS), another ID related to IGF2 down-regulation at 11p15.5 region. We show that 14q32.2 hypomethylation affects expression, not only for genes at this locus but also for other imprinted genes, and especially lowers IGF2 levels at 11p15.5. Furthermore, expression of nonimprinted genes is also affected, some of which are also deregulated in SRS patients. These findings highlight the epigenetic regulation of gene expression at the DLK1/MEG3 domain. Expression profiling of TS14 and SRS patients highlights common signatures, which may account for the clinical overlap observed between TS14 and SRS.
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Proteínas de Unión al Calcio , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 14 , Metilación de ADN , Epigénesis Genética , Impresión Genómica , Proteínas de la Membrana , Síndrome de Silver-Russell , Proteínas de Unión al Calcio/biosíntesis , Proteínas de Unión al Calcio/genética , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 11/metabolismo , Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 14/metabolismo , Femenino , Humanos , Masculino , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/metabolismoRESUMEN
Context: Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal and postnatal growth retardation, early feeding difficulties) and molecular overlap. Objective: To describe the clinical overlap between SRS and TS and extensively study the molecular aspects of TS. Patients: We retrospectively collected data on 28 patients with disruption of the 14q32.2 imprinted region, identified in our center, and performed extensive molecular analysis. Results: Seventeen (60.7%) patients showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Most patients (72.7%) had a Netchine-Harbison SRS clinical scoring system ≥4/6, and consistent with a clinical diagnosis of SRS. The mean age at puberty onset was 7.2 years in girls and 9.6 years in boys; 37.5% had premature pubarche. The body mass index of all patients increased before pubarche and/or the onset of puberty. Multilocus analysis identified multiple methylation defects in 58.8% of patients. We identified four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation. Conclusions: Most patients with 14q32.2 disruption fulfill the criteria for a clinical diagnosis of SRS. These clinical data suggest similar management of patients with TS and SRS, with special attention to their young age at the onset of puberty and early increase of body mass index.
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Trastornos de los Cromosomas/genética , Cromosomas Humanos Par 14/genética , Síndrome de Silver-Russell/genética , Adolescente , Adulto , Proteínas de Unión al Calcio , Niño , Preescolar , Deleción Cromosómica , Trastornos de los Cromosomas/diagnóstico , Metilación de ADN/genética , Diagnóstico Diferencial , Femenino , Impresión Genómica/genética , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Proteínas de la Membrana/genética , Fenotipo , Pubertad Precoz/genética , ARN Largo no Codificante/genética , Estudios Retrospectivos , Síndrome de Silver-Russell/diagnóstico , Síndrome , Disomía Uniparental , Adulto JovenRESUMEN
PurposeFetal growth is a complex process involving maternal, placental and fetal factors. The etiology of fetal growth retardation remains unknown in many cases. The aim of this study is to identify novel human mutations and genes related to Silver-Russell syndrome (SRS), a syndromic form of fetal growth retardation, usually caused by epigenetic downregulation of the potent fetal growth factor IGF2.MethodsWhole-exome sequencing was carried out on members of an SRS familial case. The candidate gene from the familial case and two other genes were screened by targeted high-throughput sequencing in a large cohort of suspected SRS patients. Functional experiments were then used to link these genes into a regulatory pathway.ResultsWe report the first mutations of the PLAG1 gene in humans, as well as new mutations in HMGA2 and IGF2 in six sporadic and/or familial cases of SRS. We demonstrate that HMGA2 regulates IGF2 expression through PLAG1 and in a PLAG1-independent manner.ConclusionGenetic defects of the HMGA2-PLAG1-IGF2 pathway can lead to fetal and postnatal growth restriction, highlighting the role of this oncogenic pathway in the fine regulation of physiological fetal/postnatal growth. This work defines new genetic causes of SRS, important for genetic counseling.
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Proteínas de Unión al ADN/genética , Retardo del Crecimiento Fetal/genética , Retardo del Crecimiento Fetal/metabolismo , Predisposición Genética a la Enfermedad , Variación Genética , Proteína HMGA2/genética , Factor II del Crecimiento Similar a la Insulina/genética , Línea Celular , Proteínas de Unión al ADN/metabolismo , Epigénesis Genética , Facies , Femenino , Retardo del Crecimiento Fetal/diagnóstico , Regulación del Desarrollo de la Expresión Génica , Estudios de Asociación Genética , Genotipo , Gráficos de Crecimiento , Proteína HMGA2/metabolismo , Humanos , Factor II del Crecimiento Similar a la Insulina/metabolismo , Modelos Biológicos , Mutación , Linaje , Transducción de Señal , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/metabolismo , Secuenciación Completa del GenomaRESUMEN
OBJECTIVES: Nutritional management of children with Silver-Russell syndrome (SRS) is crucial, especially before initiating growth hormone therapy. Since cyproheptadine (CYP) has been reported to be orexigenic, we retrospectively investigated the effects of CYP on changes in weight and height in patients with SRS. METHODS: Anthropometric parameters (weight [W], length or height [H], weight on expected weight for height [W/H], and body mass index) were recorded for 34 children with SRS receiving CYP. We specifically analyzed the anthropometric parameters (expressed in median) in a group of 23 patients treated with CYP at baseline (M0-CYP) and every 3 months (M3 to M12-CYP) after the initiation of CYP treatment. RESULTS: The 23 children with SRS treated by CYP only had weight stagnation during the months preceding the start of treatment. Anthropometric parameters, especially the weight, differed significantly between M0-CYP and all other times (M3, M6, M9, M12-CYP). After 1 year of treatment, a gain in overall length/height and weight was observed (W: +1.1 standard deviations from the mean [SDS]; H: +0.5 SDS). At M3, significant improvements in W/H (74.9% vs 79.3% [Pâ=â0.01]) and body mass index (-3.4 vs -2.4 SDS [Pâ=â0.001]) were also observed. Twenty-one patients (91%) improved their weight by at least +0.5 SDS, and 12 (52%) by at least +1 SDS. CONCLUSIONS: Our results show that CYP can be effective in patients with SRS with significant improvements in growth velocity and nutritional status before initiation of growth hormone therapy. Further prospective studies are required to confirm these results.
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Desarrollo Infantil/efectos de los fármacos , Ciproheptadina/uso terapéutico , Fármacos Gastrointestinales/uso terapéutico , Síndrome de Silver-Russell/tratamiento farmacológico , Antropometría/métodos , Preescolar , Femenino , Estudios de Seguimiento , Trastornos del Crecimiento/tratamiento farmacológico , Trastornos del Crecimiento/etiología , Humanos , Lactante , Masculino , Estudios Retrospectivos , Síndrome de Silver-Russell/fisiopatologíaRESUMEN
BACKGROUND: The 11p15 region contains two clusters of imprinted genes. Opposite genetic and epigenetic anomalies of this region result in two distinct growth disturbance syndromes: Beckwith-Wiedemann (BWS) and Silver-Russell syndromes (SRS). Cytogenetic rearrangements within this region represent less than 3% of SRS and BWS cases. Among these, 11p15 duplications were infrequently reported and interpretation of their pathogenic effects is complex. OBJECTIVES: To report cytogenetic and methylation analyses in a cohort of patients with SRS/BWS carrying 11p15 duplications and establish genotype/phenotype correlations. METHODS: From a cohort of patients with SRS/BWS with an abnormal methylation profile (using ASMM-RTQ-PCR), we used SNP-arrays to identify and map the 11p15 duplications. We report 19 new patients with SRS (n=9) and BWS (n=10) carrying de novo or familial 11p15 duplications, which completely or partially span either both telomeric and centromeric domains or only one domain. RESULTS: Large duplications involving one complete domain or both domains are associated with either SRS or BWS, depending on the parental origin of the duplication. Genotype-phenotype correlation studies of partial duplications within the telomeric domain demonstrate the prominent role of IGF2, rather than H19, in the control of growth. Furthermore, it highlights the role of CDKN1C within the centromeric domain and suggests that the expected overexpression of KCNQ1OT1 from the paternal allele (in partial paternal duplications, excluding CDKN1C) does not affect the expression of CDKN1C. CONCLUSIONS: The phenotype associated with 11p15 duplications depends on the size, genetic content, parental inheritance and imprinting status. Identification of these rare duplications is crucial for genetic counselling.
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Síndrome de Beckwith-Wiedemann/genética , Duplicación de Gen/genética , Impresión Molecular , Síndrome de Silver-Russell/genética , Adulto , Síndrome de Beckwith-Wiedemann/patología , Centrómero/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 11/genética , Inhibidor p57 de las Quinasas Dependientes de la Ciclina/genética , Análisis Citogenético , Femenino , Humanos , Factor II del Crecimiento Similar a la Insulina/genética , Masculino , Mutación , Fenotipo , Síndrome de Silver-Russell/patología , Telómero/genéticaRESUMEN
This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.
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Manejo de la Enfermedad , Internacionalidad , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/terapia , Hormona Liberadora de Gonadotropina/uso terapéutico , Hormona de Crecimiento Humana/uso terapéutico , Humanos , Síndrome de Silver-Russell/metabolismoRESUMEN
The 11p15 region harbors the IGF2/H19 imprinted domain, implicated in fetal and postnatal growth. Silver-Russell syndrome (SRS) is characterized by fetal and postnatal growth failure, and is caused principally by hypomethylation of the 11p15 imprinting control region 1 (ICR1). However, the mechanisms leading to ICR1 hypomethylation remain unknown. Maternally inherited genetic defects affecting the ICR1 domain have been associated with ICR1 hypermethylation and Beckwith-Wiedemann syndrome (an overgrowth syndrome, the clinical and molecular mirror of SRS), and paternal deletions of IGF2 enhancers have been detected in four SRS patients. However, no paternal deletions of ICR1 have ever been associated with hypomethylation of the IGF2/H19 domain in SRS. We screened for new genetic defects within the ICR1 in a cohort of 234 SRS patients with hypomethylated IGF2/H19 domain. We report deletions close to the boundaries of ICR1 on the paternal allele in one familial and two sporadic cases of SRS with ICR1 hypomethylation. These deletions are associated with hypomethylation of the remaining CBS, and decreased IGF2 expression. These results suggest that these regions are most likely required to maintain methylation after fertilization. We estimate these anomalies to occur in about 1% of SRS cases with ICR1 hypomethylation.
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Cromosomas Humanos Par 11 , Metilación de ADN , Impresión Genómica , Factor II del Crecimiento Similar a la Insulina/genética , ARN Largo no Codificante/genética , Eliminación de Secuencia , Síndrome de Silver-Russell/genética , Preescolar , Femenino , Fibroblastos , Expresión Génica , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Masculino , LinajeRESUMEN
Patient-support organizations can facilitate a significant change in the way rare disorders are approached. Besides connecting families with each other and directing patients to experienced medical specialists, these groups, by collaborating with government initiatives like COST, can effect the direction and funding of rare disease research. By concentrating the rare disease patient population and funneling them to specific centers of excellence, these organizations help build specialists' experience and their study populations. It requires a basic spirit of collaboration, driven parent leaders, a well-organized support platform, sources of funding, supportive clinical and research professionals and finally an effective method of collecting and disseminating information. Silver-Russell Syndrome is an excellent example of a rare disorder that has become better recognized, understood and treated because patient-support organizations, using the internet as a critical tool, have worked together with clinical care/research specialists and public funding agencies to build collaboration.
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Síndrome de Silver-Russell , Humanos , Enfermedades RarasRESUMEN
BACKGROUND: Multiple clinical scoring systems have been proposed for Silver-Russell syndrome (SRS). Here we aimed to test a clinical scoring system for SRS and to analyse the correlation between (epi)genotype and phenotype. SUBJECTS AND METHODS: Sixty-nine patients were examined by two physicians. Clinical scores were generated for all patients, with a new, six-item scoring system: (1) small for gestational age, birth length and/or weight ≤-2SDS, (2) postnatal growth retardation (height ≤-2SDS), (3) relative macrocephaly at birth, (4) body asymmetry, (5) feeding difficulties and/or body mass index (BMI) ≤-2SDS in toddlers; (6) protruding forehead at the age of 1-3â years. Subjects were considered to have likely SRS if they met at least four of these six criteria. Molecular investigations were performed blind to the clinical data. RESULTS: The 69 patients were classified into two groups (Likely-SRS (n=60), Unlikely-SRS (n=9)). Forty-six Likely-SRS patients (76.7%) displayed either 11p15 ICR1 hypomethylation (n=35; 58.3%) or maternal UPD of chromosome 7 (mUPD7) (n=11; 18.3%). Eight Unlikely-SRS patients had neither ICR1 hypomethylation nor mUPD7, whereas one patient had mUPD7. The clinical score and molecular results yielded four groups that differed significantly overall and for individual scoring system factors. Further molecular screening led identifying chromosomal abnormalities in Likely-SRS-double-negative and Unlikely-SRS groups. Four Likely-SRS-double negative patients carried a DLK1/GTL2 IG-DMR hypomethylation, a mUPD16; a mUPD20 and a de novo 1q21 microdeletion. CONCLUSIONS: This new scoring system is very sensitive (98%) for the detection of patients with SRS with demonstrated molecular abnormalities. Given its clinical and molecular heterogeneity, SRS could be considered as a spectrum.
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Genotipo , Fenotipo , Proyectos de Investigación/normas , Síndrome de Silver-Russell/genética , Síndrome de Silver-Russell/patología , Peso al Nacer/fisiología , Índice de Masa Corporal , Frente/anomalías , Crecimiento/fisiología , Humanos , Megalencefalia/patología , Estudios ProspectivosRESUMEN
Russell-Silver Syndrome (RSS) is a prenatal and postnatal growth retardation syndrome caused mainly by 11p15 ICR1 hypomethylation. Clinical presentation is heterogeneous in RSS patients with 11p15 ICR1 hypomethylation. We previously identified a subset of RSS patients with 11p15 ICR1 and multilocus hypomethylation. Here, we examine the relationships between IGF2 expression, 11p15 ICR1 methylation, and multilocus imprinting defects in various cell types from 39 RSS patients with 11p15 ICR1 hypomethylation in leukocyte DNA. 11p15 ICR1 hypomethylation was more pronounced in leukocytes than in buccal mucosa cells. Skin fibroblast IGF2 expression was correlated with the degree of ICR1 hypomethylation. Different tissue-specific multilocus methylation defects coexisted in 38% of cases, with some loci hypomethylated and others hypermethylated within the same cell type in some cases. Our new results suggest that tissue-specific epigenotypes may lead to clinical heterogeneity in RSS.
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Cromosomas Humanos Par 11/genética , Metilación de ADN , Impresión Genómica , Factor II del Crecimiento Similar a la Insulina/genética , Síndrome de Silver-Russell/genética , Adulto , Niño , Preescolar , Epitelio/metabolismo , Fibroblastos/metabolismo , Expresión Génica , Humanos , Recién Nacido , Leucocitos/metabolismo , Mucosa Bucal/metabolismo , Especificidad de Órganos , Piel/metabolismoAsunto(s)
Síndrome de Creutzfeldt-Jakob/inducido químicamente , Hormona de Crecimiento Humana/efectos adversos , Enfermedad Iatrogénica , Priones/patogenicidad , Adulto , Cadáver , Síndrome de Creutzfeldt-Jakob/patología , Resultado Fatal , Hormona de Crecimiento Humana/aislamiento & purificación , Humanos , Periodo de Incubación de Enfermedades Infecciosas , Masculino , Priones/aislamiento & purificaciónRESUMEN
CONTEXT: Patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency typically reach a final adult height well below their mid-parental target height. OBJECTIVE: The objective of this study was to examine whether GH alone or in combination with an LHRH analog (LHRHa) improved the final adult height in patients with CAH. DESIGN: The study was a nonrandomized prospective study. SETTING: The study was conducted at two university hospitals in New York City, NY. PARTICIPANTS: Thirty-four patients with CAH treated with GH participated in this study. Nineteen males and 15 females who were predicted to be more than 2 SD below their mid-parental target height or more than 2 SD below the population mean received GH until reaching final adult height. In addition to GH, 27 patients (16 males, 11 females) were also treated with an LHRHa. INTERVENTION: The mean duration of GH treatment was 5.6 ± 1.8 yr in males and 4.5 ± 1.6 yr in females. The mean duration of LHRHa therapy was 3.7 ± 1.7 yr for both sexes. MAIN OUTCOME MEASURES: The primary endpoint variables were final adult height, final height discrepancy, and gain in height. RESULTS: Males reached a significantly higher final adult height (172.0 ± 4.8 cm) than their initial predicted height (162.8 ± 7.7 cm) (P < 0.00001). Females also reached a significantly higher final adult height (162.2 ± 5.3 cm) than initially predicted (151.7 ± 5.2 cm) (P < 0.0000001). Mean gain in height was 9.2 ± 6.7 cm in males and 10.5 ± 3.7 cm in females. CONCLUSION: Our results indicate that GH alone or in combination with LHRHa improves final adult height in patients with CAH.
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Hiperplasia Suprarrenal Congénita/fisiopatología , Hiperplasia Suprarrenal Congénita/terapia , Estatura/fisiología , Hormona de Crecimiento Humana/uso terapéutico , Adolescente , Adulto , Niño , Femenino , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/uso terapéutico , Humanos , Masculino , Selección de Paciente , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Final adult height is often compromised in children with congenital adrenal hyperplasia (CAH). This study examines the impact of GH and LHRH analog (LHRHa) on final adult height in patients with CAH due to 21-hydroxylase deficiency. Fourteen patients with CAH (eight males, six females) predicted to be more than 1.0 sd below their midparental target height received GH and LHRHa until final height. Each patient was matched at the start of GH therapy to a CAH patient treated only with glucocorticoids according to type of CAH, sex, and chronological age. Mean age, bone age, height, height prediction, and target height were the same in both groups at the beginning of GH therapy. Mean duration of GH treatment was 4.4 +/- 1.5 yr. Mean duration of LHRHa therapy was 4.2 +/- 2.0 yr. In the treatment group, final height sd score of -0.4 + 0.8 was significantly greater than both the initial prediction of -1.5 +/- 0.9 (P < 0.0001) and the final height sd score of the untreated group of -1.4 +/- 1.1 (P = 0.01). Our results indicate that the combination of GH and LHRHa improves final adult height in patients with CAH.
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Hiperplasia Suprarrenal Congénita/tratamiento farmacológico , Estatura/efectos de los fármacos , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/uso terapéutico , Hormona de Crecimiento Humana/uso terapéutico , Adolescente , Adulto , Niño , Femenino , Crecimiento/efectos de los fármacos , Crecimiento/fisiología , Humanos , Masculino , Resultado del TratamientoRESUMEN
The growth hormone releasing hormone receptor (GHRHR) plays a critical role in growth. We identified three nominally unrelated kindreds harboring the identical mutation (E72X) in GHRHR, the gene that encodes GHRHR; all three families originated in the Indian subcontinent. Because of the relative geographic proximity of these populations, we employed haplotype analysis in the region of GHRHR to determine the likelihood that this mutation occurred in a common ancestor rather than having occurred on separate occasions in different individuals. Members of all three kindreds segregating the E72X mutation were genotyped for highly polymorphic dinucleotide repeat microsatellites in a 15.5 centimorgan (cM) region around GHRHR on chromosome 7p15. We conclude that the affected individuals share a common ancestor, and we use the association with linked markers to estimate the age of this unique mutation.