Wit JM, Ranke MB, Kelnar CJH (eds): ESPE classification of paediatric endocrine diagnosis. 1. Short stature. Horm Res 2007;68(supp 2):1 5

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1 Wit JM, Ranke MB, Kelnar CJH (eds): ESPE classification of paediatric endocrine diagnosis. 1. Short stature. Horm Res 2007;68(supp 2):1 5 ESPE Code Diagnosis OMIM ICD-10 1 SHORT STATURE 1 1A PRIMARY GROWTH FAILURE 1A.1 Clinically defined syndromes 1A.1a Syndromes classified elsewhere: 45,X/46,XY disorder of sex development (4A.1) 45,X and variants with female phenotype ((Ulrich)-Turner syndrome) (14A.5) Phenotypic male with X/XY mosaicism (14A.4) 18q deletion syndrome (14A.1) Aarskog-Scott syndrome (14B.1) Bloom syndrome (14B.6) Cornelia de Lange syndrome (14B.9) DiGeorge syndrome (velocardiofacial syndrome) (14B.10) Down syndrome (14A.2) Kabuki makeup syndrome (14C.4f) Noonan syndrome (14B.24) Prader-Willi-Labhart syndrome (14B.25) Von Recklinghausen s disease (neurofibromatosis type 1) (14B.27) Rubinstein-Taybi syndrome (14B.29) Silver-Russell syndrome (14B.31) Williams-Beuren syndrome (14B.37) 1A.1y Other specified syndromes, e.g. Three M slender-boned dwarfism, Seckel syndrome, Mulibrey nanism 1A.1z Other syndromes associated with short stature, unspecified P05.1 1A.2 Small for gestational age (SGA) with failure of catch-up growth 2 1A.2a Disorders classified elsewhere: IGF-I deficiency (1B.4e) IGF resistance (1B.4f) 1A.2y Due to known cause (specify), e.g. prenatal infection, drugs, P smoking, alcohol 1A.2z Idiopathic 1A.3 Skeletal dysplasias (constitutional disorders of bone) 3 Q77, Q78 1A.3a Achondroplasia group (group 1) 4 1A.3a.1 Achondroplasia # A.3a.2 Hypochondroplasia # Short Stature 1

2 ESPE Code Diagnosis OMIM ICD-10 1A.3a.8 Other specified disorders included in this group (thanatophoric dysplasia, SADDAN) 1A.3b Type II collagenopathies (COL2A1 defects) (group 8) 1A.3b.1 Spondyloepiphyseal dysplasia congenita # A.3b.8 Other specified disorders in this group 1A.3c Mesomelic dysplasias (group 16) 1A.3c.1 Dyschondrosteosis (Leri-Weill and other defects in the SHOX # gene, e.g. in children without dysmorphic features) [primary: 14B.19] 1A.3c.2 Langer type (homozygous dyschondrosteosis) # A.3c.8 Other specified disorders included in this group 1A.3d Dysostosis multiplex group (group 22) 1A.3d.1 Mucopolysaccharidosis (type IH, IS, II VII) E76 1A.3d.2 Mucolipidosis (type II and III) # E77.0 # A.3d.8 Other specified disorders included in this group 1A.3e Dysplasias with decreased bone density (group 24) 1A.3e.1 Osteogenesis imperfecta I VI [primary: 12D.1b] 1A.3e.8 Other specified disorders included in this group 1A.3f Dysplasias with defective mineralisation (group 25) 1A.3f.1 Hypophosphatasia # A.3f.2 Hypophosphataemic rickets [primary 12C.2] # A.3f.8 Other specified disorders included in this group 1A.3y Disorders included in other groups (2 7, 9 15, 17 21, 23, 26 33) 1A.3z Other skeletal dysplasia, unspecified 1B SECONDARY GROWTH FAILURE 1B.1 Insufficient nutrient intake (malnutrition) E B.2 Disorders in organ systems 1B.2a Cardiac disorders Q B.2b Pulmonary disorders, e.g. cystic fibrosis J40 99 (E84) 1B.2c Liver disorders K B.2d Intestinal disorders, e.g. Crohn s disease, malabsorption syndromes, short bowel syndrome K50 52 K B.2e Renal disorders, e.g. Fanconi syndrome, renal acidosis N10 19 N B.2f Chronic anaemia D B.2g Multiorgan disorders ESPE Classification of Paediatric Endocrine Diagnoses 2

3 ESPE Code Diagnosis OMIM ICD-10 1B.2h Muscular and neurological disorders, e.g. Duchenne muscular dystrophy, congenital myotonia G B.2i Connective tissue diseases, e.g. juvenile arthritis M08 1B.2y Other specified organ or systemic disorders 1B.3 Growth hormone deficiency (secondary IGF deficiency) 5 E23.0 In case of multiple pituitary deficiencies, classify the various deficiencies separately: ACTH deficiency (6A.1) TSH deficiency (6A.2) Gonadotropin deficiency (6A.3) Prolactin deficiency (6A.4) Vasopressin deficiency (diabetes insipidus) (13A.1) 1B.3a Congenital growth hormone deficiency E23.0 1B.3a.0 Disorders classified elsewhere: Associated with complex syndromes: Fanconi renotubular syndrome (14B.13) Rieger syndrome (14B.28) Kabuki make-up syndrome (14C.4f) 1B.3a.1 Associated with other complex syndromes: ectodactyly-ectodermal dysplasia clefting syndrome E23.0 1B.3a.2 Known genetic defects E23.0 1B.3a.2a HESX1 * B.3a.2b LHX3 * B.3a.2c LHX4 * B.3a.2d PROP1 * B.3a.2e POU1F B.3a.2f GHRHR * B.3a.2g GH B.3a.2y Other specified genetic defects 1B.3a.3 Associated with cerebral or facial malformations, e.g. septooptic dysplasia [primary 6E.1a], empty sella syndrome, solitary central maxillary incisor syndrome, mid-line palateal cleft, Q04.4 Q37.9 O35.0 arachnoid cyst, congenital hydrocephalus, hypoplastic anterior pituitary + missing stalk + ectopic posterior pituitary (HME) Excluded: Known genetic defects (1B.3a.2) 1B.3a.4 Associated with prenatal infection, e.g. rubella P35.0 1B.3a.8 Associated with other specified disorders E23.0 1B.3a.9 Idiopathic E23.0 1B.3a.9a Classical idiopathic growth hormone deficiency 6 1B.3a.9b Neurosecretory dysfunction 7 Short Stature 3

4 ESPE Code Diagnosis OMIM ICD-10 1B.3b Acquired growth hormone deficiency E23.0 1B.3b.1 Craniopharyngioma D44.4 1B.3b.2 Other pituitary tumours, e.g. germinoma, hamartoma M9064/3 1B.3b.3 Cranial tumours distant from the pituitary/hypothalamic area, e.g. astrocytoma, ependymoma, glioma, medulloblastoma, nasopharyngeal tumour C71 M9400/3 M9391/3 M9380/3 M9470/3 IB.3b.4 Tumours outside the cranium, e.g. leukaemia, lymphoma C91 96 IB.3b.5 Head trauma S06 IB.3b.6 Central nervous system infection G01 08 IB.3b.7 Granulomatous diseases, e.g. histiocytosis D76 IB.3b.8 Vascular anomaly Q28 IB.3b.9 Other causes, unspecified E23.0 1B.4 Other disorders of the growth hormone-igf axis (primary IGF-I deficiency and resistance) 1B.4a Bio-inactive growth hormone (Kowarski syndrome) 8 # E34.3 1B.4b Abnormalities of the growth hormone receptor # E34.3 (growth hormone insensitivity syndrome, Laron syndrome) 1B.4c Abnormalities of GH signal transduction, e.g. STAT5B defect # E34.3 1B.4d ALS (acid-labile subunit) deficiency E34.3 1B.4e IGF-I deficiency # E34.3 1B.4f IGF resistance (IGF1R defects, postreceptor defects) # E34.3 1B.4z Other disorders, unspecified 1B.5 Other endocrine disorders 1B.5a Disorders classified elsewhere: Cushing syndrome (8C.1) Hypothyroidism (7A) Leprechaunism (11A.3b.2) Poorly controlled diabetes mellitus, Mauriac syndrome (14C.2) 1B.5b Short adult stature caused by accelerated bone maturation, e.g. precocious puberty (3A), hyperthyroidism (7B), congenital adrenal hyperplasia (8A.1), exogenous estrogens or androgens (3A.2d) 1B.5y Other specified disorders E34.3 1B.6 Metabolic disorders 1B.6a Disorders classified elsewhere: Disorders of calcium and phosphorus metabolism (1A.3 and 12) 1B.6b Disorders of carbohydrate metabolism E74 1B.6c Disorders of lipid metabolism E75 ESPE Classification of Paediatric Endocrine Diagnoses 4

5 ESPE Code Diagnosis OMIM ICD-10 1B.6d Disorders of protein metabolism E B.6y Other specified metabolic disorders E B.6z Other metabolic disorders, unspecified E88 1B.7 Psychosocial E34.3 1B.7a Psychosocial (emotional) deprivation 9 T74 1B.7b Anorexia nervosa F50 1B.7c Depression F32.9 1B.7y Other specified psychosocial causes E34.3 1B.8 Iatrogenic 1B.8a Systemic glucocorticoid therapy [primary 8C.1c] T38.0 1B.8b Local glucocorticoid therapy (inhalation, intestinal, other) T49.0 1B.8c Other medication T B.8d Treatment of childhood malignancy 1B.8d.1 Total body irradiation T66 1B.8d.2 Chemotherapy T45.1 1B.8y Other specified iatrogenic causes T78.9 1C IDIOPATHIC SHORT STATURE 10 E34.3 1C.1 Familial (idiopathic) short stature 11 E34.3 1C.1a With normal pubertal onset 1C.1b With delayed pubertal onset 1C.1c Onset of puberty not yet known 12 1C.1d Onset of puberty unknown 1C.2 Non-familial (idiopathic) short stature 13 E34.3 1C.2a With normal pubertal onset 1C.2b With delayed pubertal onset (constitutional delay in growth and puberty, or constitutional delay in growth and adolescence) 1C.2c Onset of puberty not yet known 14 1C.2d Onset of puberty unknown Short Stature 5

6 1 Short stature Comments: Short stature is defined as a height below 2.0 SDS (2.3rd percentile) for a given age, sex and population. It is the result of impaired bone growth in the foregoing period, which is expressed in terms of a reduced length/height velocity in at least some period of life (including the intrauterine period). In some conditions growth velocity is only diminished early in life (e.g. in children born SGA with failure of catch-up growth), in other conditions growth velocity is continuously low (e.g. in children with complete growth hormone deficiency). The terms growth delay and growth retardation are also frequently used with the same intention as short stature. In this diagnostic classification an abnormally low height velocity is also classified under the general heading of Short stature. The causes of short stature are varied and differ with respect to aetiology and pathogenesis. To our present knowledge, disorders of the hormonal system account only for a minority of children with short stature. Since growth disorders are the key symptom of many hormonal abnormalities and since children with growth disorders are commonly presented to the paediatric endocrinologist, disorders presenting with short/tall stature are part of this classification system. 2 Small for gestational age (SGA) with failure of catch-up growth Phenotype: Short stature and birth length and/or weight below 2 SDS (or below the 2.3rd centile) for gestational age for the reference population. Comments: There is some discussion about the use of the terms intrauterine growth retardation (IUGR) and small for gestational age (SGA). There appears now some consensus that the term IUGR implies impaired fetal growth and should be considered a prenatal diagnosis. SGA describes birth length and/or weight in relation to gestational age and is a post-partum diagnosis. The majority of babies born SGA (approximately 85%) catch up in height (within 2 3 years) and will not be short in childhood or in adulthood, although their mean height is somewhat lower than expected for target height. The 15% of babies who do not catch-up (height < 2 SDS after 2 or 3 years) are termed SGA with failure to catch-up, or shortly SGA. Those who failed to catch-up by 2 years are at high risk of remaining short in later life. Thus, the term SGA is purely descriptive, and is a working diagnosis for children born small and continuing to be short. In most cases there is no known aetiology and/or pathogenesis. 3 Skeletal dysplasias (constitutional disorders of bone) Comments: Skeletal dysplasias exist in a great variety and are commonly associated with short stature. Traditionally, the diagnosis was established based on the clinical appearance during development and conventional X-ray findings. More recently, the classification of skeletal dysplasias has been based upon the expanding understanding of the pathophysiology of bone development and the discovery of the underlying molecular genetic defects. This has resulted in an International nomenclature and classification of osteochondrodysplasias (1997) published by the International Working Group on Constitutional Diseases of Bone [Am J Med Genet 1998;79: ] and a more recent update [Hall CM: International nosology and classification of constitutional disorders of bone (2001). Am J Med Genet 2002;113:65 77]. In this classification 33 groups are presented, each including various clinical entities. For the ESPE Classification of Paediatric Endocrine Diagnoses just 6 groups out of the 33 are mentioned specifically. For a more detailed classification we refer to the most recent paper on International Nosology and Classification. ESPE Classification of Paediatric Endocrine Diagnoses 6

7 4 Achondroplasia, hypochondroplasia Phenotype: Achondroplasia and hypochondroplasia are disorders characterised by disproportionate short stature with rhizomelic limb shortening. They are commonly caused by mutations in the tyrosine kinase domain of the fibroblast growth factor receptor 3 (FGFR3) gene. However, in the absence of these mutations the diagnosis may still be confirmed by typical radiological findings. 5 Growth hormone deficiency (GHD) Synonym (if combined with other deficiencies): Hypothalamo-hypopituitarism, multiple congenital pituitary hormone deficiency. Phenotype: Growth retardation, retarded bone age, hypoglycaemia, truncal obesity, symptoms of neonatal hypoglycaemia and those of associated anomalies, e.g. midline defects, micropenis. Comments: An impaired secretion of GH in children is causally associated with impaired growth, changes of the anthropometrical characteristics (e.g. normal proportions, relatively large head) and the composition of the body (e.g. sarcopenia, excess of body fat) as well as functional abnormalities (e.g. hypoglycaemia). Classifications based on functional investigations of GH secretion and action have allowed some degree of understanding of the role of the various components of the GH-IGF-I axis. Functional investigations include measurements of GH by means of various assays (immunoassays, bioassays), determination of GH levels after various exogenous stimuli, the analysis of spontaneously secreted GH, measurements of GH dependent factors (IGF-I, IGFBP-3; ALS), and the biochemical response to exogenous GH (e.g. IGF generation). In addition to the difficulty of conducting such functional tests, the limitations of standardisation and the lack of normative data has hindered a concise interpretation of the obtained data and their interplay until today. New imaging tools (CT, MRT) allow the description of qualitative and quantitative anatomical anomalies of the pituitary region. A higher resolution and functional imaging is likely to lead to a further dimension in describing more subtle abnormalities. Discoveries by means of molecular genetics allow the description of abnormalities in the development of the pituitary and its ability to produce and secrete GH and other trophic hormones. Classifications systems of GHD may also consider whether GHD is congenital and follows a certain pattern of inheritance or whether it is acquired. 6 Classical Idiopathic GHD Comments: Idiopathic GHD (i.e. no aetiology is established) is still the most common form of GHD. It appears trivial, but nevertheless important to note that every reasonable effort should be made to exclude diagnoses other than GHD beforehand. The key diagnostic tools to establish the diagnosis are blood GH measurements collected under spontaneous conditions or after physiological or pharmacological stimuli (e.g. arginine). In order to avoid falsely positive results these tests should be conducted under strict standardisation and under the least stressful conditions for the child. Since it is assumed that test results are prone to be falsely low, at least two independent tests are required to confirm the diagnosis. A cut-off level of 20 mu/l (equivalent to 10, 7.7 or 6.7 μg/l, depending on the standard used; 1 mg = 2, 2.6 or 3 IU) for GH in serum or plasma is generally accepted as a guideline. This cut-off may, however, vary according to the applied GH assay, the test procedures used and the normative references available. It is obvious that all available methods should be applied to increase the likelihood of the diagnosis of GHD. Normal stature, a normal height velocity and a normal bone age are probably not completely excluding the diagnosis of idiopathic GHD, but make its presence quite unlikely. Likewise normal/high-normal IGF-I (IGFBP-3, ALS) levels are also not supportive of the diagnosis. An MRI of the pituitary area is an essential part of the diagnostic process of GHD. A small Short Stature 7

8 anterior pituitary or a pituitary abnormality are not an a priori proof of a disturbed GH secretion, but are likely to provide evidence that the biochemically established diagnosis of GHD is correct. With greater refinement in our diagnostic arsenal less cases with GHD will be classified idiopathic. 7 Neurosecretory dysfunction (NSD) Comments: The term NSD describes a specific situation, in which GH levels observed during stimulation tests are normal, but spontaneously secreted GH is low. This situation was first described in children who had been treated with radiotherapy to the cranium as part of treatment for a malignancy. In this situation NSD can be seen as a special form of organic GHD. However, this situation was also found to exist in children without such a history. Critics have emphasised that there is a great day-to-day variation in spontaneous GH secretion, and that spontaneous GH secretion is sometimes very low in normally growing children. 8 Bioinactive GH (Kowarski syndrome) Comments: Bioinactive GH can be suspected in children clinically resembling classical GH, with low circulating IGF-I levels but with normal GH secretion based on immunoassay measurements. Treatment with GH leads to an increase in IGF-I levels and a growth response to GH. It can be assumed that one reason for bioinactive GH is a congenital structural abnormality of GH, which impairs/abolishes interaction with the GH receptor and subsequent signal transduction. Sophisticated methods (e.g. RRA, bioassay, gene analyses) are required to prove such an entity. Up to 2006, only a few welldocumented cases have been published. 9 Psychosocial deprivation Synonym: Emotional deprivation. Phenotype: Behavioural abnormalities, such as apathy, watchfulness, autoerotic activity, delayed developmental behaviour. Poor growth at home, catch-up growth in hospital or foster home. Reversible GH deficiency has been described. 10 Idiopathic short stature (ISS) Comments: The definition of ISS (previously also called normal variant short stature, or non-gh-deficient short stature) is based on the exclusion of other likely causes of short stature, as well as the following minimal criteria: normal size at birth (> 2 SDS) for gestational age normal body proportions no evidence of chronic organic disease no psychiatric disorder or severe emotional disturbance normal food intake no evidence of endocrine deficiency. The tempo of growth throughout the growth process may either be slow or normal. Reference: Ranke MB: Horm Res 1996;45: Familial (idiopathic) short stature (FSS) Phenotype: Height for chronological age is below the 2.3rd centile (< 2 SDS) for given age, sex and population, and height is within the normal range for parental height. The parent-specific lower limit of height (SDS) can be calculated in various ways. ESPE Classification of Paediatric Endocrine Diagnoses 8

9 References: Preece MA: Horm Res 1996;45:56 58; Ranke MB: Horm Res 1996;45:64 66; Hermanussen M, Cole J: Horm Res 2003;59: ; Wit JM: Horm Res 2007;67(suppl 1): Familial short stature, onset of puberty not yet known Comments: A short prepubertal child who is not short for target height with an age below the upper limit of the normal age at pubertal onset is classified here. In some cases, a positive family history for pubertal delay and a delayed bone age suggest the syndrome of constitutional delay in growth and adolescence, although in typical cases height in childhood is lower than expected for target height. As soon as the onset of puberty (G2 or B2) is known, the patient can be classified as 1C.1a or 1C.1b. 13 Non-familial (idiopathic) short stature (NFSS) Phenotype: Height for chronological age is below the 2.3rd centile (< 2 SDS) for given age, sex and population and height is below the normal range for parental height. Comments: Non-familial short stature (NFSS) is a purely descriptive term. The majority of children with NFSS have a condition usually labelled as constitutional delay in growth and adolescence (CDGA) or small/delay. In CDGA short stature is combined with a retardation of the tempo of growth. When signs of puberty are delayed beyond the normal age range, CDGA can be diagnosed. Before pubertal age, a delay in bone maturity may be suggestive for CDGA, but strictly speaking CDGA can only be diagnosed if puberty is indeed delayed. In these cases the diagnosis NFSS with pubertal onset not yet known is more appropriate. 14 Non-familial idiopathic short stature, onset of puberty not yet known A short prepubertal child who is short for parental height with an age below the upper limit of the normal age at pubertal onset is classified here. In some cases, a positive family history for pubertal delay and a delayed bone age suggest the syndrome of constitutional delay in growth and adolescence. As soon as the onset of puberty (G2 or B2) is known, the patient can be classified as 1C.2a or 1C.2b. Short Stature 9