Diffuse cutaneous mastocytosis has been diagnosed in all patients described so far. It is generally characterized by hyperpigmented macules or papules that are symmetrically distributed over the trunk, and less so over the limbs, neck, and scalp [1]. Pruritus does not seem to be a universal feature of HBS, but has been reported for one of the affected children: The girl described by Wolach et al. had episodes of intense pruritus. Urtication was observed when lesions were stroked, which has been interpreted as a positive Darier's sign [2]. The authors reported remarkable dermographism, and similar findings have been made in later cases [1] [3].

In HBS patients, cutaneous mastocytosis is accompanied by distinct malformations and dysmorphic features [1] [2] [3]. Those features that are mentioned in the name of the disease - short stature and microtia - have been observed in two and one out of three cases only, while microcephaly seems to be a more prevalent symptom. All three girls who have been diagnosed with HBS were found to be microcephalic. Frontal bossing, prominent supraorbital ridges, and slight proptosis have been noted, and at least one of the patients was found to have a triangular face. The patients also had upslanted palpebral fissures, part of them with epicanthal folds, a wide nasal bridge, and a long, prominent nose. Hypoplasic nares were reported in two cases, while micrognathia and a highly arched palate were uniformly observed. Micrognathia may be accentuated by a receding chin. One of the girls had a particularly long tongue, another had full lips. Additionally, scoliosis, syndactyly, fifth finger clinodactyly or camptodactyly, and asymmetric, small feet were present. One of the patients showed nail hypodysplasia.

Conductive hearing loss has been diagnosed in two out of three cases. It has been related to atretic ear canals and pinnae, without functional impairment of the middle and inner ear [2]. In one of these patients, hearing impairment was aggravated by concurrent sensorineural hearing loss [3].

Besides these symptoms, the parents of the two younger children reported feeding problems. At least two patients displayed abnormal reflexes. Slow newborn reflexes, decreased deep tendon reflexes, an absent swallowing reflex, and an exaggerated gag reflex have been reported [2] [3]. Hypotonia was observed in all cases, and at least one of the girls suffered from convulsions. This patient was found to be mentally retarded, as was one of the other girls who didn't display seizures [1] [3].

• Feeding Difficulties

  […] brain ventricles * High arched palate * Impaired hearing * Infant feeding difficulty * Large fontanelle * Mental retardation * Scoliosis * Seizures * Short stature * Small ears * Small head * Small jaw Prevention - Hennekam Beemer syndrome Not supplied [checkorphan.org]

  Classification developmental, genetic Phenotypes Abnormality of metabolism/homeostasis; Abnormality of skin pigmentation; Autosomal recessive inheritance; Clinodactyly; Conductive hearing impairment; Cutaneous mastocytosis; Dermatographic urticaria; Feeding [dev.mousephenotype.org]

  Feeding difficulties MedGen UID: 65429 • Concept ID: C0232466 • Finding Impaired ability to eat related to problems gathering food and getting ready to suck, chew, or swallow it. [ncbi.nlm.nih.gov]

  Salpietro et al. (2009) reported a 16-year-old girl, born of nonconsanguineous parents, who at 3 years of age developed diffuse macules and papules on the neck and trunk, but did not have pruritus, feeding difficulties, or recurrent infections. [omim.org]

• Family History of Deafness

  Interestingly, mastocytosis has only been observed in these two patients, but there was a family history of deafness. [symptoma.com]

• Poor Feeding

  […] difficulties Feeding problems Poor feeding [ more ] 0011968 Generalized hypotonia Decreased muscle tone Low muscle tone [ more ] 0001290 Underdeveloped nasal alae Underdeveloped tissue around nostril 0000430 Showing of 58 | Last updated: 3/1/2020 If [rarediseases.info.nih.gov]

• Receding Chin

  She had a large anterior fontanel, slight proptosis, upward slanting palpebral fissures, highly arched palate, receding chin, and clinodactyly of the fifth fingers. [omim.org]

  Micrognathia may be accentuated by a receding chin. One of the girls had a particularly long tongue, another had full lips. Additionally, scoliosis, syndactyly, fifth finger clinodactyly or camptodactyly, and asymmetric, small feet were present. [symptoma.com]

• Hearing Impairment

  This condition may lead to hearing impairment, as has been diagnosed in two out of three HBS cases. [symptoma.com]

  Overview A very rare syndrome characterized mainly by short stature, abnormal skin pigmentation, small ears and hearing impairment. [checkorphan.org]

  Loss and Microtia Meier-Gorlin syndrome + Mengel Konigsmark Syndrome Metaphyseal Dysostosis, Mental Retardation, and Conductive Deafness Microtia with Nasolacrimal Duct Imperforation and Eye Coloboma Microtia, Hearing Impairment, and Cleft Palate Microtia [rgd.mcw.edu]

  hearing impairment; Cutaneous mastocytosis; Dermatographic urticaria; Feeding difficulties; Generalized hypotonia; High palate; Intellectual disability; Microcephaly; Micrognathia; Microtia; Scoliosis; Short stature; Underdeveloped nasal alae; Upslanted [dev.mousephenotype.org]

• Muscle Hypotonia

  Physical examination showed muscle hypotonia and clumsiness. The father’s (patient 44) height was 180 cm, his birth length was 57 cm (3.3 SDS). [karger.com]

• Muscle Tone Abnormalities

  Generalized hypotonia MedGen UID: 346841 • Concept ID: C1858120 • Finding Generalized muscular hypotonia (abnormally low muscle tone). [ncbi.nlm.nih.gov]

• Abnormal Reflex

  At least two patients displayed abnormal reflexes. Slow newborn reflexes, decreased deep tendon reflexes, an absent swallowing reflex, and an exaggerated gag reflex have been reported. [symptoma.com]

The concurrent presence of cutaneous mastocytosis and additional features as described above warrant the clinical diagnosis of HBS. Salpietro and colleagues, who reported the third and hitherto last patient, proposed cutaneous mastocytosis, microcephaly, microtia and/or conductive hearing loss as the minimal diagnostic criteria [1].

Dysmorphism may be recognized at birth, and diffuse skin pigmentation may also be present in the neonate [2] [3]. In other cases, cutaneous mastocytosis wasn't developed until the age of 3 [1]. The diagnosis of cutaneous mastocytosis is based on the histological examination of skin biopsy samples, and there's no need for additional measures if no doubts remain as to systemic involvement [4]. With regards to the histological features of cutaneous mastocytosis, prominent mast cell infiltration is the most striking finding. Mast cells typically aggregate around blood vessels, and they may be associated with eosinophils [5]. Epidermal acanthosis and hyperkeratosis may also be observed [2].

Further diagnostics are required only in the case of organomegaly, elevated serum tryptase levels, and/or unexpectedly severe symptoms. Molecular testing of peripheral blood cells for the KIT D816V mutation may be realized as the first step towards a more reliable diagnosis. The specificity of this test is close to 100%, and in the absence of this mutation, systemic mastocytosis is highly unlikely [6]. If mutations of the KIT gene - D816V or others - are confirmed, biopsy samples should be obtained from the bone marrow or any extracutaneous organ suspicious of mast cell infiltration. Mast cell immunophenotyping may then be realized as well as, in the case of eosinophilia, molecular testing for FIP1L1-PDGFRA fusion [7]. No such findings have yet been related to HBS; the involvement of extracutaneous organs is not to be expected in HBS patients, and neither diagnostic imaging nor laboratory analyses are likely to reveal anomalies beyond the malformations described in the previous paragraph [1] [2].

The molecular background of HBS remains unclear, and thus, clinical findings cannot yet be corroborated by genetic studies. To date, we only know that HBS patients have a normal karyotype.

Due to the knowledge gaps regarding the etiology and pathophysiology of the disease, causal treatment is not available, and only symptomatic therapies can be offered to HBS patients:

• Symptomatic therapy of cutaneous mastocytosis aims at suppressing skin and systemic mast cell mediator-related symptoms. It may comprise the avoidance of triggers, if any are recognized, and the use of antihistamines, steroids, and cromolyn. Of note, remission at puberty is seen in the majority of children diagnosed with non-syndromic cutaneous mastocytosis, and the use of chemotherapy, including kinase inhibitors, is strongly discouraged in these patients unless severe hematological disease is present [5]. It is, however, unknown whether spontaneous remission may occur in HBS patients, and whether or not they may benefit from cytoreductive drugs. What's more, none of the case reports comprises therapeutic indications, and little is known about the response of children with HBS-related mastocytosis to any type of pharmacological treatment.
• Bone conduction auditory devices have been used to improve the hearing abilities of the girl who has been diagnosed in the early 1990s [2]. Although hearing-aid technology has come a long way since these days, bone-conducting hearing devices are still the gold standard for the treatment of congenital conductive hearing loss due to malformations of the external ear [8]. To support normal speech and language development, HBS patients with bilateral hearing impairment should be provided a properly fitted and programmed hearing aid as early as possible.
• Surgical interventions and orthopedic measures may be employed to correct malformations and reduce their impact on the patients' quality of life. These procedures must be adapted to the individual patient's needs, and no general recommendations can be given.

Mental retardation, hearing impairment, and malformations associated with HBS may have a profound impact on the patients' quality of life, and it seems feasible that microcephaly may lead to neurological deficits that are incompatible with survival. To date, such a severe course of the disease has not been described. Indeed, there are no data regarding the long-term development of HBS patients, and little can be said regarding their life expectancy or the likelihood of spontaneous remission. Unfortunately, one of the girls died at 8 years of age from bronchopneumonia [3]. The other patients might have reached mid-adulthood by now, but no follow-ups have been published [1] [2].

HBS is assumed to be inherited in an autosomal recessive manner. This assumption is based on the mostly sporadic incidence of the disease, with one of the patients having consanguineous parents [2]. None of the girls had a family history of a similar disorder [1] [2] [3]. Still, the underlying mutation has not been identified so far.

HBS is a very rare syndrome. Only three cases have been described in the literature: a Sephardic Jewish girl who was born to consanguineous parents from Libya [2], a Dutch girl born to unrelated parents [3], and a third girl whose ethnic origins have not been disclosed. Her parents were unrelated, too [1]. Even though the disease has never been reported in males, the very low number of cases does not allow for the conclusion that HBS couldn't be observed in boys. Similarly, no statements can be made with regard to possible preferences for ethnicities or geographic regions.

The pathogenesis of cutaneous mastocytosis in children is not well understood, and the majority of patients does not present mutations of the proto-oncogene KIT [4] [5]. Besides the publications on HBS, few case reports have been published about congenital syndromes comprising cutaneous mastocytosis and hearing impairment. None of these case reports included information as to the genetic background of the respective disease.

Trevisan and colleagues described two siblings who presented with cutaneous mastocytosis and sensorineural hearing loss. Interestingly, mastocytosis has only been observed in these two patients, but there was a family history of deafness [9]. This case illustrates the possibility of distinct traits being inherited independently, or at least involving multiple, yet interacting genes. With regard to HBS, the possibility of a polygenic disorder should also be considered.

Similarly, the patient described by Ina et al. presented with cutaneous mastocytosis and sensorineural hearing loss. Computed tomography and magnetic resonance imaging were carried out to identify the causes of deafness. Skeletal anomalies could not be detected, but there were bilateral symmetric, subcortically located, high-signal intensity lesions in the white matter of temporo-occipital and fronto-parietal lobes [10]. These findings are in contrast to what has been observed in HBS patients, where neurological deficits and possibly seizures are generally attributed to microcephaly.

Under the assumption that HBS is a genetic disorder that is inherited in a recessive pattern, the avoidance of sexual activities between family members and consanguineous marriage may help to further reduce its incidence. Awareness should be raised in the general population, and people should be educated about the possible consequences of adhering to deeply rooted traditions that increase the likelihood of hereditary disorders to occur.

The combination of cutaneous mastocytosis, short stature, conductive hearing loss, and microtia has first been described by Wolach et al. in 1990. These authors speculated they were describing " a new congenital malformation, most probably of genetic origin" [2]. In 1992, a second case was reported. Hennekam and Beemer wrote about a girl suffering from "skin mastocytosis, hearing loss, microcephaly, mild dysmorphic features, and severe mental retardation" [3]. There were many similarities between both patients, but also important differences. In contrast to the first patient, the second one was mentally retarded, a fact that had a profound impact on her quality of life. It was not until 17 years later, when a third case report was published. The patient described by Salpietro and colleagues was diagnosed with cutaneous mastocytosis and displayed some of those features observed by Wolach et al., while others coincided with the second case. This patient displayed microtia but was not hearing impaired; she was found to be microcephalic and mentally retarded but had grown to a normal height [1]. Based on their observations, the Italian group suggested cutaneous mastocytosis, microcephaly, microtia and/or conductive hearing loss as the minimal diagnostic criteria for this syndrome, which is nowadays commonly referred to as HBS.

Cutaneous mastocytosis - short stature - conductive hearing loss - microtia is a rare syndrome. In the literature, it is generally referred to as Hennekam-Beemer syndrome (HBS), and only three cases have been described to date. Little is known about the causes of the disease, which is assumed to be of genetic origin. Accordingly, there are no specific tests, and the diagnosis is made clinically. The minimal diagnostic criteria for this syndrome are:

• Cutaneous mastocytosis. This term refers to a skin disorder characterized by the presence of excessive mast cells in the dermis. Affected children typically present with hyperpigmented macules or papules, and they may suffer from urticaria and pruritus.
• Microcephaly, i.e., an abnormally small head. Microcephaly may interfere with the development of the central nervous system and induce mental retardation and seizures, although not all HBS patients were found to be mentally handicapped.
• Microtia and/or conductive hearing loss. Microtia describes a congenital malformation of the pinna and may be accompanied by defects of the ear canal. This condition may lead to hearing impairment, as has been diagnosed in two out of three HBS cases.

Affected children may have additional malformations and dysmorphic features, e.g., upslanted palpebral fissures, a wide nasal bridge, underdeveloped nostrils, a small mouth, and a highly arched palate. Scoliosis may also be found, and parents may encounter feeding problems with their hypotonic children.

Only symptomatic therapy can be offered to HBS patients, which may comprise the pharmacological regulation of mast cell degranulation, the use of bone-conducting hearing devices to improve the patient's hearing abilities, and possibly surgical procedures and the use of orthopedic aids.

1. Salpietro CD, Briuglia S, Cutrupi MC, Gallizzi R, Rigoli L, Dallapiccola B. Apparent third patient with cutaneous mastocytosis, microcephaly, conductive hearing loss, and microtia. Am J Med Genet A. 2009; 149a(10):2270-2273.
2. Wolach B, Raas-Rothschild A, Metzker A, et al. Skin mastocytosis with short stature, conductive hearing loss and microtia: a new syndrome. Clin Genet. 1990; 37(1):64-68.
3. Hennekam RC, Beemer FA. Skin mastocytosis, hearing loss and mental retardation. Clin Dysmorphol. 1992; 1(2):85-88.
4. Valent P. Diagnostic evaluation and classification of mastocytosis. Immunol Allergy Clin North Am. 2006; 26(3):515-534.
5. Castells M, Metcalfe DD, Escribano L. Diagnosis and treatment of cutaneous mastocytosis in children: practical recommendations. Am J Clin Dermatol. 2011; 12(4):259-270.
6. Carter MC, Bai Y, Ruiz-Esteves KN, et al. Detection of KIT D816V in peripheral blood of children with manifestations of cutaneous mastocytosis suggests systemic disease. Br J Haematol. 2018; 183(5):775-782.
7. Gotlib J, Gerds AT, Bose P, et al. Systemic Mastocytosis, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018; 16(12):1500-1537.
8. Dougherty W, Kesser BW. Management of Conductive Hearing Loss in Children. Otolaryngol Clin North Am. 2015; 48(6):955-974.
9. Trevisan G, Pauluzzi P, Gatti A, Semeraro A. Familial mastocytosis associated with neurosensory deafness. J Eur Acad Dermatol Venereol. 2000; 14(2):119-122.
10. Ina A, Altintas DU, Yilmaz M, et al. Congenital mastocytosis associated with neurosensory deafness. Pediatr Dermatol. 2007; 24(4):460-462.