Holoprosencephaly–polydactyly/pseudotrisomy 13: a presentation of two new cases and a review of the literature

Abstract

Patients with a combination of holoprosencephaly and polydactyly, but with apparently normal chromosomes, may be clinically diagnosed with holoprosencephaly–polydactyly syndrome (HPS), also termed pseudotrisomy 13. However, the criteria for HPS have been controversial since the advent of the diagnostic term, and a clear understanding of the condition lacks definitive delineation. We review the historical and current perspectives on the condition and analyze findings in 40 patients with apparent HPS, including cases from the literature and two previously unreported patients. Overall, our analysis suggests previously unrecognized trends in patients diagnosed with HPS. Specifically, there appears to be a higher prevalence of visceral anomalies, most significantly cardiac and genitourinary, but also with increased gastrointestinal, pulmonary, adrenal, skeletal, and renal abnormalities, in patients with HPS. Although these visceral anomalies may not be essential for the identification of HPS, clinicians should be aware of the presence of such characteristics in these patients to optimize management and help establish etiologies.

Introduction

Holoprosencephaly (HPE) is the most common malformation of the human forebrain, occurring in one in 250 gestations, although only approximately one in 10 000 live-born infants present with the condition because of the high proportion of intrauterine lethality (Orioli and Castilla, 2010). In addition to characteristic structural brain abnormalities, patients typically have accompanying midline facial anomalies, which range from cyclopia or synophthalmia at the most severe end of the spectrum to findings such as hypotelorism and a single central maxillary incisor in less severely affected patients. The causes of HPE are highly heterogeneous. HPE may occur as one component in a syndrome, may be because of cytogenetic anomalies, or may occur because of mutations in over 10 identified genes associated with nonchromosomal, nonsyndromic HPE (Pineda-Alvarez et al., 2010; Solomon et al., 2010).

HPE is classified into four major types, depending on the degree of severity of brain malformations: alobar (the most severe type), semilobar, lobar, and the more recently described middle interhemispheric variant-type HPE (Hahn and Barnes, 2010). Patients may also have ‘microform’ HPE, in which conventional neuroimaging shows no brain anomalies consistent with frank HPE, but patients may have subtle facial features consistent with a midline deficit. Many patients with microform HPE are identified because of the birth of a severely affected relative (Solomon et al., 2010).

Although the causes of some types of syndromic HPE have been elucidated, others remain less well delineated. Holoprosencephaly–polydactyly syndrome (HPS) is one of the less understood entities, although several lines of enquiry provide interesting hints. Classically diagnosed in patients with a combination of HPE, polydactyly, and apparently normal chromosomes, the criteria for HPS, also called pseudotrisomy 13, have been controversial since the use of the term began (Cohen, 1989a, 1989b, 1989c; Hewitt et al., 1989). Here, we analyze findings in 40 patients with apparent HPS and review the historical and current perspectives on the condition. Our analysis shows key trends in HPS. First, normal chromosomes as a required criterion may not be justified, as cytogenetic abnormalities have been discovered in some patients, pointing to possible genetic causes. Second, along these lines, cytogenetic analysis, including newer microarray and large-scale sequencing techniques, may allow increased molecular understanding of the cause of HPS. Third, clinicians should be aware that patients may have other anomalies (e.g. cardiac and genitourinary), which are highly associated with HPS and should be evaluated for when encountering a patient with HPS.

Diagnostic controversies

There have been difficulties both in defining HPS and in clearly showing its existence as a unified phenotype. The similarity to hydrolethalus syndrome led to the proposal that they are manifestations of the same disorder (Bachman et al., 1990). Others disagreed, arguing that HPS is a separate entity (Cohen and Gorlin, 1992). Further delineation of the syndrome led to the suggestion that pseudotrisomy 13 can manifest without polydactyly, an anomaly previously believed essential to the diagnosis (Ramos-Arroyo et al., 1994). In an attempt to resolve the debate, new criteria were established, taking into account sporadic and familial types of HPS. According to this formulation, a sporadic occurrence would fulfill the diagnostic criteria in the case of a normal karyotype and one of the following: HPE and postaxial polydactyly; HPE and other abnormalities not including polydactyly; or postaxial polydactyly, brain abnormalities such as microcephaly, agenesis of corpus callosum, and/or hydrocephalus, as well as other abnormalities. Patients with familial HPS/pseudotrisomy 13 would require an affected sibling to have a normal karyotype and the same clinical criteria outlined for sporadic cases would apply (Lurie and Wulfsberg, 1993).

The controversy grew with the discovery that a normal karyotype, the third classic diagnostic criterion, may not always be evident in patients with HPS. Of the 40 cases described in Table 1, only 82% have seemingly normal karyotypes. Further, there may be underappreciated cytogenetic anomalies not apparent on conventional chromosome analysis that may account for the presence of HPS (Hewitt et al., 1989; Brown et al., 1993; Chen et al., 1998, 2005; Chang, 2003; Koolen et al., 2006; Bendavid et al., 2010; Marquis-Nicholson et al., 2011). As an aggregate, these developments are not surprising, given the growing availability and use of high-density microarrays. Microalterations on chromosome 13 may be the cause of HPS in some. Evidence suggests that the region in question lies in chromosome arm 13q, which includes the locus for ZIC2, a gene frequently mutated in HPE (Hewitt et al., 1989; Brown et al., 1993; Koolen et al., 2006). Other cytogenetic anomalies in patients with pseudotrisomy 13 include the partial deletion of chromosome 8p and duplication of 5q35.1 (Chen et al., 1998, 2005; Chang, 2003; Koolen et al., 2006). Another study described multiple (21) long contiguous stretches of homozygosity in a patient showing the features of pseudotrisomy 13 (Marquis-Nicholson et al., 2011).

Table 1.

Cases of holoprosencephaly–polydactyly syndrome/pseudotrisomy 13

Patient	Craniofacial features	Neuroanatomical description	Limb features	Genetic testinga	Other abnormal features	Specifics of other abnormal features	References
1	Microphthalmia, facial cleft	Hydrocephalus, HPE, ACC	Peripheral hypoplasia of left  arm, tetramelic octodactyly	NS	Cardiac	Consanguinity, cardiac defects	Grote et al. (1984)
2	Maxillary agenesis, cleft  palate	Alobar HPE, hydrocephalus	Bilateral upper limb postaxial  polydactyly, club foot	46,XY	Cardiac, genitourinary	ASD, VSD, cardiac valve  abnormalities, microphallus,  cryptorchidism	Young and Madders (1987)
3	Hypotelorism, malformed  ears	Hydrocephalus	Bilateral 2–3 toe syndactyly,  right hand postaxial  polydactyly, club foot	46,XY	Genitourinary	Ambiguous genitalia, imperforate  anus	Atkin (1988)
4	Cyclopia, proboscis	Alobar HPE	Left foot postaxial polydactyly	46,XY	Genitourinary	Ambiguous genitalia	Atkin (1988)
5	Anophthalmia	Alobar HPE, hydrocephalus, occipital  encephalocele, hypoplastic  cerebellum and vermis	Postaxial polydactyly of the  hands	46,XY	Pulmonary	Consanguinity, bilobed lungs	Donnai (1988)
6	Hypotelorism, suborbital  proboscis	Alobar HPE, hydrocephalus,  hypoplasia of the pituitary/thyroid  glands	Bilateral upper limb postaxial  polydactyly	46,XX	Renal	Renal dysplasia, hirtsutism	Moerman and Fryns (1988)
7	NS	HPE	Bilateral postaxial hexadactyly	NS	Other	Affected sibling	Moerman and Fryns (1988)
8	Proboscis, hypotelorism	Alobar HPE	Postaxial polydactyly	NS	Cardiac, genitourinary	Ambiguous genitalia, two vessel  cord, VSD, affected sibling	Moerman and Fryns (1988)
9	Cyclopia	Alobar HPE	Bilateral postaxial polydactyly of  upper and lower limbs	NS	Cardiac	VSD, two vessel cord	Shiota and Tanimura (1988)
10	Hypotelorism, absent nose,  cleft lip/palate	Hydrocephalus, semilobar HPE, absent  olfactory/chiasm/pituitary glands	Postaxial polydactyly in all  extremities	46,XY	Cardiac, gastrointestinal,  adrenal	Consanguinity, adrenal agenesis,  splenomegaly, heart defects,  affected sibling	Hewitt et al. (1989)
11	Microphthalmia, cleft lip,  low-set ears	Alobar HPE, occipital encephalocele,  hydrocephalus	Postaxial polydactyly of the  hands	46,XX	Pulmonary	Lung abnormalities	Meinecke (1989)
12	Hypotelorism,  microphthalmia	Hydrocephalus, absent frontal bone,  lobar HPE, dysplastic basal ganglia,  absent olfactory gland, corpus  callosum, hippocampus, cerebellum	Postaxial polydactyly in the left  hand and foot	46,XY	Gastrointestinal	Consanguinity, omphalocele,  affected sibling	Bachman et al. (1990)
13	Microphthalmia, maxillary  agenesis	Agenesis of brain structures,  hydrocephalus	Postaxial polydactyly of both the  hands and the left foot	NS	Other	Consanguinity	Bachman et al. (1990)
14	Microcephaly, large anterior  fontanelle, low-set ears,  hooked nose,  microretrognathia,  hypertelorism	Enlarged cisterna magna, fused lateral  ventricles suggestive of semilobar  HPE	Hypoplasia of the first phalanx,  left club foot, right hip  dislocation	46,XX; patient’s father  was mosaic 46XY/  46XY (2;13)  (2q24;13q33)	Cardiac, skeletal	Suggestive of consanguinity, 13  pairs of ribs, VSD, single palmar  creases	Verloes et al. (1991)
15	Single nostril, median  pseudocleft lip,  hypotelorism,  microphthalmia	Semilobar HPE, ACC, agenesis of  septum pellucidum and falx cerebri	Postaxial polydactyly of the  hands and feet	46,XY	Gastrointestinal,  genitourinary	Hypogenitalism, microphallus,  Hirschsprung’s disease,  thermoregulatory instability,  electrolyte and thyroid hormone  abnormalities	Ramaekers et al. (1989)
16	Hypotelorism, microcephaly,  hypoplastic nose, cleft  palate	Dysplastic vermis and cerebellar foci,  absent olfactory bulbs/tracts	Unilateral postaxial polydactyly  (postminimus) of the left foot	NS	Cardiac	Consanguinity, IUGR, single palmer  creases, VSD, ASD, affected  sibling	Hennekam et al. (1991)
17	Microcephaly, hypotelorism,  microphthalmia, flat  rudimentary nose,  bilateral cleft lip/palate,  low-set ears	Midline continuity of corpus striatum  and thalamus suggestive of  semilobar HPE	Not present	46,XY	Genitourinary	Consanguinity, microphallus,  cryptorchidism, affected sibling	Hennekam et al. (1991)
18	Microphthalmia, cleft lip	Seizures	Postaxial hexadactyly of the  hands	Normal karyotype, NS	Other	Consanguinity, apnea	Cohen and Gorlin (1991)
19	Porboscus, cyclopia,  microstomia, dysplastic  ears	Hydramnios, holosphere	Bilateral postaxial polydactyly of  the upper limbs	46,XY	Cardiac, adrenal	ASD, hypoplastic adrenals	Verloes et al. (1991)
20	Cleft palate, premaxillary  agenesis	NS	Bilateral postaxial polydactyly of  the upper limbs	46,XX	Cardiac, gastrointestinal	Cardiomegaly, TOGV, malrotated  gut	Verloes et al. (1991)
21	Labiopalatine cleft	Hydrocephalus, macroopthalmia,  semilobar HPE, aplasia of olfactory  gland	Bilateral postaxial polydactyly of  the upper limbs	46,XY	Cardiac, gastrointestinal,  genitourinary,  pulmonary, skeletal	Penile hypoplasia, aplasia of heart,  lungs, gallbladder, testes,  vertebral anomalies	Verloes et al. (1991)
22	NS	Hydrocephalus, alobar HPE, abnormal  gyration	Bilateral postaxial polydactyly of  the upper and lower limbs	46,XY	Other	Consanguinity	Verloes et al. (1991)
23	Absent ocular globes, single  nostril	NS	Bilateral postaxial polydactyly	46,XY	Cardiac, genitourinary,  adrenal	Ambiguous genitalia, VSD,  hypoplastic adrenal glands	Verloes et al. (1991)
24	Cleft lip, hypotelerism, flat  nose, absence of  premaxilla, low-set ears,  micrognathia	Semilobar HPE	Right hand postaxial  polydactyly, upper limb  shortness, radial hypoplasia,  bilateral partial 2–3  syndactyly of the toes	46,XX	Cardiac, genitourinary	AV canal defect, lung abnormalities,  bicornuate uterus	Boles et al. (1992)
25	Micro/anophthalmia	HPE	Postaxial polydactyly	Normal karyotype, NS	Cardiac, renal	Heart defects, renal hypoplasia,  ambiguous genitalia	Higgins and Minnick (1992)
26	Cleft lip/palate	HPE	Postaxial polydactyly	Normal karyotype, NS	Cardiac, renal	Heart defects, renal hypoplasia	Higgins and Minnick (1992)
27	Cleft lip/palate,  hypotelorism, absent  nose	Semilobar HPE, absent olfactory lobes  and optic nerves	Not present	46,XY; mother mosaic  45,X/46,XX/47,XXX/  48,XXXX	Other	Sibling with poly/hexadactyly	Seller et al. (1993)
28	Microcephaly, upslanted  fissure, exophthalmos,  hypotelorism, cleft  lip/palate, abnormal ears	Alobar HPE, seizures	Not present	46,XX	Cardiac, genitourinary	Heart anomalies, uterine duplication	Ramos-Arroyo et al. (1994)
29	Microcephalic,  microphthalmia,  hypotelorism,  cebocephalus,  pseudocleft palate	Alobar HPE, absent olfactory and optic  nerves, dysgenesis of hypopituitary,	NS	46,XX	Gastrointestinal, pulmonary,  adrenal	Acrocyanosis, choanal atresia, lung  and spleen abnormalities,  dysgenesis of thyroid and adrenal  glands	Koolen et al. (2006)
30	Hypotelorism, pseudocleft  palate	Alobar HPE with fused thalamus,  absent olfactory and optic nerves,  dysgenesis of hypopituitary	Preaxial polydactyly of the left  hand	46,XX	Gastrointestinal, adrenal	Choanal atresia, dysgenesis of  thyroid and adrenal glands	Koolen et al. (2006)
31	Hypotelorism, nasal  hypoplasia, midface cleft,  premaxillary agenesis,  low-set ears	Alobar HPE, absent olfactory and optic  nerves	Postaxial polydactyly of the right  hand	46,XX, partial trisomy  13q (13q22→qter)  and partial  monosomy 8p  (8p23.3→pter)	Cardiac	Hypoplastic left heart	Chang (2003)
32	Macrocephaly,  microagnathia, cleft  lip/palate, hypertelorism,  low-set ears, broad nose	Hydrocephalus, midline  brain defect NS	Club foot	46,XY	Cardiac	Laryngeal stenosis, ASD	Cakir et al. (2006)
33	Microcephaly, hypotelorism,  flat rudimentary nose,  single nasal opening, high  palate, dysplastic low-set  ears	Alobar HPE	Postaxial polydactyly of the  upper limbs	46,XX	Cardiac, gastrointestinal,  genitourinary	Single creases, ASD, ventricular  hypoplasia, duodenal stenosis	Ahmet et al. (2006)
34	Facial dysmorphic features,  NS	Lobar HPE, seizures	Right preaxial polydactyly	dup5q35.1	Cardiac, genitourinary	Vesicoureteral reflux, VSD	Chen et al. (2005)
35	Hypotelorism, cleft lip, flat  nose, single nostril, low-set  ears	Semilobar HPE, hydrocephalus	Postaxial polydactyly in all  extremities	46,XY	Cardiac, pulmonary	Consanguinity, lung abnormalities,  VSD	Utine et al. (2008)
36	Macrocephalic, extropia,  hypoplastic  ala nasae	Semilobar HPE, hydrocephalus	Polysyndactyly in all  extremities	46,XY; negative for  mutations in   SHH, ZIC2, SIX3,  TGIF, GLI3,   FBXWII, DISP1.  Normal DHCR7	Other	Hemangioma, hypotonia, motor  delay	Cordero et al. (2008)
37	Cleft lip/palate	Semilobar HPE	Bilateral syndactyly and  hypoplasia of the toes	46XY, negative for  mutations in SHH,  TGIF, SIX3, GLI2,   TIP73L, DHCR7	Genitourinary	Ectopic testes, microphallus	Zechi-Ceide et al. (2009)
38	Hypotelorism, cleft lip/  palate, brachycephalic  contour of the skull, flat  nose with midline groove  and shallow dimples in  place of the nostrils, low-  set ears	HPE, rudimentary falx and cerebral  hemispheres replaced by a  holosphere, interhemispheric fissure	Postaxial polydactyly, partial  syndactyly	46,XX, with 21 noted  LCSHs	Cardiac, pulmonary, adrenal	VSD, incomplete lobation of the  right lung with rudimentary  horizontal and oblique fissures,  adrenal hypoplasia, possible  affected siblings	Marquis-Nicholson et al. (2011)
39	Cleft lip/palate, flat nose	HPE	Hexadactyly, thumb hypoplasia,  right radial deviation	46,XY, no deletion of  7q36 or   22q11.2, no  cholesterol   abnormalities,  negative SHH, ZIC2,  SIX3, TGIF	Cardiac, genitourinary,  skeletal	Tetralogy of Fallot, hypospadias,  vertebral anomalies, hypotonia	This report
40	Proboscis	HPE	Polydactyly, NS	Normal karyotype,  negative for   mutations in SHH,  ZIC2, SIX3, TGIF,  GLI2, and normal   oligonucleotide  array CGH   (Signature)	Cardiac,  skeletal	Cardiac and vertebral anomalies	This report

The amount of information was variable for patients, and details are given as specified in the original sources; hence, the terminology may differ slightly between patients so as not to alter data through misinterpretation. ACC, agenesis of the corpus callosum; ASD, atrial septal defect; AV, atrioventricular; HPE, holoprosencephaly; IUGR, intrauterine growth restriction; LCSHs, long contiguous stretches of homozygosity; NS, not specified; TOGV, transposition of the great vessels; VSD, ventricular septal defect.

^aBy conventional chromosome analysis (karyotype) unless otherwise noted.

Theories of causation

The molecular pathogenesis of HPS is poorly understood and is likely complex. Traditionally, HPE is thought to be a result of a loss-of-function mutation, while polydactyly is thought to be a result of a gain-of-function mutation (Clark et al., 2001). One hypothesis for why both loss-of-function and gain-of-function effects may result from the same pleiotropic mutation is that the response to the signals from the gene(s) responsible for HPS may differ because of varying embryologic patterning of the brain and limbs. Alternatively, the phenotype may result from two or more mutations involving different genes or an as yet undiscovered contiguous gene syndrome, resulting in brain and limb anomalies (Cordero et al., 2008).

Sonic hedgehog (SHH) is a key molecule in the pathogenesis of HPE and many genes implicated in HPE are tied to the SHH signaling pathway (Solomon et al., 2010). The presence of HPE because of diverse causes such as Smith–Lemli–Opitz syndrome, maternal alcohol use, and the use of the cholesterol-lowering statin class of medications during pregnancy may all be tied to SHH signaling (Lanoue et al., 1997; Edison and Muenke, 2004; Li et al., 2007). Further, aberrant SHH signaling is also associated with disorders that manifest polydactyly, including Pallister–Hall syndrome, Greig cephalopolysyndactyly, and isolated postaxial polydactyly (Ming et al., 1998). Thus, it is highly plausible that hedgehog signaling may be involved in HPS despite the fact that mutations in the SHH gene itself have not yet been identified in patients with HPS.

Nonetheless, it is likely that HPS is a heterogeneous disorder, as shown by theories of HPS inheritance. Among the cases in Table 1, 28% describe parental consanguinity, leading to the suspicion of autosomal recessive inheritance in some cases (Ramaekers et al., 1989; Bachman et al., 1990; Brown et al., 1993; Ahmet et al., 2006; Marquis-Nicholson et al., 2011). Eighteen percent of cases were found to have an affected sibling with HPS. However, the possibility of an X-linked or an autosomal dominant mode of inheritance cannot be ruled out (Atkin, 1988; Seller et al., 1993). Although more males overall (45%) are reported than females (28%), both sexes are significantly represented. Finally, germline mosaicism is well described in isolated HPE, and must not be ignored when discussing possible inheritance patterns (Ramaekers et al., 1989; Solomon et al., 2010).

Differential diagnosis

With the broader inclusion criteria described above, some cases significantly overlap with other disorders, which may lead to difficulties in establishing a diagnosis. Conditions that share common characteristics with HPS include hydrolethalus syndrome and trisomy 13. Other conditions may have overlapping features, such as Smith–Lemli–Opitz syndrome, Meckel syndrome, and Pallister–Hall syndrome, necessitating a full clinical genetic consultation to help determine whether or not these other diagnoses should be pursued by targeted testing.

Genetic evaluation in a few recent cases of HPS ruled out some of these disorders in at least the tested individuals (Cordero et al., 2008; Zechi-Ceide et al., 2009). However, it must be stated that with many of the patients described in our analysis, it is difficult to exclude all overlapping conditions, as not all have had the same clinical diagnostic work-up or extensive molecular testing. In fact, it may well be that patients diagnosed with HPS represent a causally heterogeneous group of patients. As molecular understanding of diseases advances, the aggregate diagnosis of HPS may dissolve into separate conditions.

Materials and methods

We report on two patients who participated in our National Human Genome Research Institute Institutional Review Board approved protocol on HPE, with appropriate consent obtained from participating families. Samples and available clinical information were sent to our lab from referring clinicians, and sequencing of HPE-associated genes was performed through standard dideoxynucleotide sequencing (methods described in detail in Pineda-Alvarez et al., 2010).

We analyzed findings in 38 additional previously reported patients with apparent HPS using Pubmed and Medline as search mechanisms with the search terms including ‘holoprosencephaly’, ‘HPE’, ‘pseudotrisomy’, ‘pseudotrisomy 13’, and ‘holoprosencephaly and polydactyly’.

Results

New patient reports

Patient 39 was a 1-year-old male first child of nonconsanguineous parents of western European descent who had an unremarkable family history. Neuroimaging during gestation showed a partial fusion in the rostral basal ganglia believed to represent mild HPE, as well as a lipoma of the corpus callosum. Postnatal MRI confirmed these findings, and indicated that a single maxillary central incisor was not present. Birth measurements showed that head circumference, height, and weight were all below the third centile for gestational age; measurements at 12 months of age showed a weight between the 10th and the 25th centile, body length between the 50th and the 75th centile, and microcephaly, with occipito-frontal head circumference less than the third centile. Facial features were consistent with HPE, with marked midface hypoplasia, a flattened nasal bridge, and a midline cleft lip and palate. Limb anomalies included left upper extremity radial deviation and thumb hypoplasia and evidence of right upper extremity preaxial hexadactyly (status-post surgical correction at the time of examination). Additional anomalies included tetralogy of Fallot, multiple fused and hemivertebrae resulting in scoliosis, hypospadias, and micropenis. The patient showed generalized hypotonia and severe motor delay. Laboratory analysis indicated evidence of diabetes insipidus, but no other endocrinological abnormalities. Karyotype analysis, fluorescence in-situ hybridization for 7q36 and 22q11.2, as well as quantitative cholesterol levels were all normal. Sequence analysis of SHH, ZIC2, SIX3, and TGIF indicated no mutations. An oligonucleotide array CGH (Signature) was not performed.

Patient 40 was diagnosed in utero with HPS. Imaging indicated neuroanatomical anomalies consistent with severe HPE, as well as the presence of a proboscis, polydactyly, cardiac defects, and hemivertebrae. Full autopsy was not performed and further data are not available. Karyotype analysis and oligonucleotide array CGH (Signature) showed no abnormalities. Sequence analysis of SHH, ZIC2, SIX3, TGIF, and GLI2 indicated no mutations.

Combined findings

Patients diagnosed with HPS are presented in Table 1. The availability of clinical details was variable. Slightly less than 80% of patients were described as having classic HPE and 92% overall were found to have some type of central nervous system defect. Brain anomalies were not recorded in 8% of the patients; however, facial features in these cases were consistent with a diagnosis of HPE. These features include eye abnormalities, such as hypotelorism (70%), cleft lip and/or palate (53%), nose anomalies consistent with HPE (28%), and, separately, proboscis (10%). In patients in whom the HPE type was described, there was a skewing toward severe forms. Thirty-three percent of the patients had alobar, 25% had semilobar, and 5% had lobar HPE.

Polydactyly was described in 80% of patients, whereas 93% had some type of limb abnormality, including polydactyly. At least 95% of patients with polydactyly had postaxial polydactyly. Although organ system defects are not believed to be essential to the diagnosis of HPS, there was a high prevalence of cardiac (58%), genitourinary (35%), gastrointestinal (20%), pulmonary (15%), adrenal (10%), skeletal (10%), and renal (8%) abnormalities (for a more detailed description of the patients, please refer to Table 1).

Discussion

Although first described over two decades ago, the definitive diagnosis of HPS remains a challenge. First, the criteria of HPE, polydactyly, and normal chromosomal analysis have served as a guideline for the diagnosis of the syndrome. A broadened list of criteria was subsequently created (Lurie and Wulfsberg, 1993). Since these criteria were established, more extensive cytogenetic methodologies have become available, leading to the discovery of distinct anomalies found on several chromosomes that may be linked to causes of HPS. Our data suggest that normal chromosomes were found in most but not all cases of HPS. Further, sequencing results from the new patients reported here lend support to the hypothesis that mutations in known and well-characterized HPE-associated genes are not common causes of HPS. With the increased use of newer genomic diagnostic techniques such as high-density microarrays and high-throughput sequencing, smaller regions of genomic variance and individual exonic mutations may be better appreciated, and may possibly lead to an improved understanding of the complex etiology of the condition. It is entirely possible that HPS will remain a unifying clinical diagnosis that can result from many possible genetic and environmental causes, as has been well described for HPE in general (Solomon et al., 2010). When a clinician considers a diagnosis of HPS, genetic studies on both a clinical and a research basis should be pursued to further understand the condition, as well as to improve the management of these patients.

Second, our data highlight a high prevalence of a variety of visceral anomalies, most significantly involving the cardiac and genitourinary systems, in patients with HPS. This prevalence of visceral anomalies in HPS appears overall higher than in HPE more generally. In a recent and impressively large study describing a cohort of over 600 European patients with HPE, 27% were found to have visceral anomalies (Mercier et al., 2011). Although perhaps not essential for the identification of HPS, clinicians should be aware of the presence of such characteristics in these patients. These findings may also point to potential causes. For example, the neuroanatomical anomalies of HPE can naturally lead to a variety of endocrinologic disturbances, but adrenal cortical development appears to be directly linked to the SHH signaling pathway (Ching and Vilain, 2009; King et al., 2009; Huang et al., 2010), implying a role for this pathway in at least some patients.

Finally, along these lines, we suggest the following for work-up of a patient in whom a clinician is considering a diagnosis of HPS: detailed clinical exam by a geneticist to assess for polydactyly and other anomalies, with further studies as indicated; neuroimaging (MRI is preferred) to establish the presence and type of HPE as well as other central nervous system anomalies; echocardiogram; renal ultrasound; conventional karyotype, with reflex microarray if the karyotype is negative; further targeted genetic testing if other conditions in the differential diagnosis appear likely; as well as consideration of research participation.