Emerging spectrum of DOCK8 deficiency in children and challenges associated with providing treatment: experience from a tertiary referral centre in India

doi:10.21203/rs.3.rs-3337352/v1

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Emerging spectrum of DOCK8 deficiency in children and challenges associated with providing treatment: experience from a tertiary referral centre in India

https://doi.org/10.21203/rs.3.rs-3337352/v1

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The study describes the course of children with DOCK8 deficiency, their stormy clinical course, discrete infection pattern, and challenges during the treatment. The retrospective study included children up to 18 years of age diagnosed to have genetically proven DOCK8 deficiency from January 2013 to January 2023. A total of nine children were included, with a median age of five years. Clinical presentations included eczema (2/9), viral infections (4/9), recurrent sinopulmonary infections (3/9), impetigo (2/9), autoimmune hemolytic anemia (1/9) and Epstein-Barr virus driven malignancy (1/9). Other infections noted were molluscum contagiosum in two children, cytomegalovirus colitis in one child, and recurrent Klebsiella pneumoniae meningitis. The outcomes of hematopoietic stem cell transplantation (HSCT) remained poor (n=5, three haploidentical HSCT, one each matched family and unrelated donor HSCT), due to early and refractory viral reactivation, with 17,00,000 copies of cytomegalovirus in one child and 8,53,95,600 copies of adenovirus in another child. Secondary late graft failure was noted in one child, two years following a matched sibling donor HSCT. The one who underwent a matched unrelated donor HSCT was doing well and was infection free. The clinical course without HSCT had been stormy, as seen in a child with Burkitt's lymphoma, who succumbed to refractory cytomegaloviral meningoencephalitis despite being in remission following chemotherapy. DOCK8 deficiency patients are included in the Hyper IgE syndrome spectrum. HSCT poses significant challenges in these children with refractory viral infections. Collaborative work and research are required to decide the optimal care for these children to guide better treatment outcomes.

DOCK8 deficiency

HSCT

treatment

course

infections

Dedicator of cytokinesis 8 (DOCK8) is a combined immunodeficiency first identified in 2004 by Engelhardt et al [1]. Out of the DOCK family of eleven proteins, DOCK8 belongs to the DOCKC category and is a large gene located on chromosome 9 [2]. It is a rare autosomal recessive disease more commonly expressed in the consanguineous marriage population [3]. DOCK8 expression is encountered in immune cells like hematopoietic stem cells and non-immune cells like the placenta, kidney, lungs, and pancreas [4].

DOCK8 deficiency was identified as an underlying pathology in patients with an autosomal recessive form of hyper IgE syndrome (AR-HIES), the autosomal dominant form being due to STAT3 deficiency (AD-HIES). The two forms of hyper IgE syndromes (Job's syndrome) have significant phenotypic differences [5, 6].

DOCK8 deficiency, a type of retinopathy, is caused by a loss of function mutation in the DOCK8 protein, which regulates the actin cytoskeleton. Actinopathies are immunodeficiencies that prevent the polymerization of actin, thus impairing cell mobility and immune synapses of hematopoietic stem cells. The DOCK8 protein is required for certain immune cells to move through dense tissues without fragmenting or dying. DOCK8 plays an important role in controlling both innate and adaptive immunity, a type of combined immunodeficiency. DOCK8 protein function in innate immunity showed that dendritic cells rely on this protein for trafficking from the skin to nearby lymph nodes, which is defective in this condition. They are also found to have decreased plasmacytoid dendritic cells in circulation with poor interferon-alpha production; all these can predispose a cell to early apoptosis. Compared to innate immunity, DOCK8 protein has several functions regarding adaptive immunity. The normal function is through its actin cytoskeleton regulation, facilitating the accumulation of adhesion molecules and cytotoxic granules at immunological synapses. When this mechanism is defective, it leads to impaired T, B, and NK cell survival [7, 8].

DOCK8 deficiency can be one of the most common differential diagnoses amongst physicians treating inborn errors of immunity (IEI). It encompasses the broad clinical features of primary immunodeficiency extending beyond recurrent infections and includes atopy, autoimmunity, and malignancy, with presentation in the early years of life, especially during infancy [9, 10]. Clinical features are characterized by eczema, recurrent respiratory and persistent viral infections predominantly affecting the skin. Apart from infections, they suffer from significant autoimmune sequelae and have an increased risk of cancer predisposition, typically viral-driven malignancies. Failure to thrive and growth stunting due to malabsorption caused by allergy, autoimmune enteropathy, and infection is a significant clinical feature in many children.

Diagnosis of DOCK8 deficiency is established by clinical features combined with laboratory findings usually confirmed by genetic analysis. Initial investigation reveals eosinophilia with an elevated IgE level. Further immunological evaluation shows low naïve CD4 + T cells, CD3+, CD8 + cells, and low IGG levels. DOCK8 expression can be evaluated through flow cytometry or western blot analysis. Genetic analysis by whole exome sequencing is confirmatory before proceeding with further definitive treatment for the child [11, 12].

The only available curative option for DOCK8 deficiency is hematopoietic stem cell transplantation (HSCT). Administration of immunoprophylaxis and screening and treating complications, including infections and malignancies, are the other primary modalities of treating children with DOCK8 deficiency for whom HSCT is not feasible.

The current study aims to analyze the varied clinical presentation of children with Dock8 deficiency, the treatment offered, and their responses.

The study was conducted in the pediatric hematology and blood and marrow transplantation unit in a tertiary referral centre. The study included children up to 18 years of age with genetically (whole exome sequence) proven DOCK8 deficiency, and included those who underwent HSCT as well as those who did not opt for transplant and were on regular follow-up. All children were on long-term prophylaxis with cotrimoxazole and itraconazole and were continued on monthly intravenous immunoglobulin (IVIG) infusions.

Data were collected retrospectively from a review of patient charts over ten years, from January 2013 to January 2023. Data was collected on patient demographics, the clinical spectrum of presentation, prevention, the medical treatment offered, infections and medications, transplantation details, if any, transplant-related outcomes, and overall outcomes in these children. Data on children who underwent HSCT included type of HSCT, donor type, source of stem cell used, T cell replete or depleted HSCT in case of haploidentical transplant, CD34 count used, engraftment details, viral reactivation, and outcomes in these children.

The institutional review board approved the study, and written informed consent was obtained from the parents/guardians of all children.

A total of nine children were included in the study. At the presentation, the youngest child was two months old, while the oldest child was eight years, with a median age of five years. Table 1 summarizes the pretransplant clinical presentation.

Table 1

Patient characteristics including presentation, infections, and outcome
Patient number	Name/sex	Age at presentation	Clinical features	Major infections	HSCT	Type of graft/donor	Alive/died
1.	N/female	4 months	CMV colitis	Disseminated CMV viremia post HSCT	Yes	TCR alpha/beta depleted haploidentical HSCT from father	Died
2.	D/female	9 months	Autoimmune hemolytic anemia	Molluscum contagiosum, disseminated adenoviral infection post HSCT	Yes	TCR alpha/beta depleted haploidentical HSCT from father	Died
3.	K/male	2 years	Recurrent impetigo, chronic diarrhea	Disseminated CMV disease post HSCT	Yes	TCR alpha/beta depleted haploidentical HSCT from father	Died
4.	S/male	4 years	Recurrent respiratory infections, Burkitts lymphoma	Disseminated CMV disease including encephalitis	No	-	Died
5.	D/female	5 years	Recurrent respiratory infections	Bronchiectasis, on home oxygen	No	-	Alive
6.	M/male	6 years	Recurrent respiratory infections, recurrent extensive impetigo	Fournier’s gangrene	No	-	alive
7.	S/male	8 years	Sibling of patient 6	Impetigo	No	-	Alive
8.	K/male	3 months	Recurrent respiratory infections and otitis media	Extensive molluscum contagiosum	Yes	Matched unrelated donor HSCT	Alive and well
9.	K/male	3 months	Recurrent Klebsiella pneumonia meningitis, otitis media	Septic shock following secondary graft failure four years post HSCT	Yes	Matched sibling donor HSCT	Died

All patients were born from third-degree consanguineous parents and presented with characteristic manifestations of DOCK8 deficiency, eczema (2/9), viral infections (4/9), food allergies (1/9), recurrent sinopulmonary infections (3/9), skin impetigo (2/9), autoimmune hemolytic anemia (1/9) and Epstein-Barr virus (EBV) driven malignancy (1/9). The viral infections encountered were molluscum contagiosum in two children, cytomegalovirus (CMV) colitis in one child, and a combination of molluscum contagiosum and herpes simplex in another child. There was also an unusual parasitic infection in one child with giardia and cryptosporidium growing in his stool culture, while another child had repeated bacterial meningitis with Klebsiella pneumoniae. Growth failure was observed in all the children in the cohort.

Any infections that were documented pre-transplant in these children were treated vigorously before taking up the child for transplant. Four children had mild to moderate clinical manifestations, and due to socioeconomic constraints, the family did not opt for HSCT. All these children were on monthly IVIG along with immunoprophylactic medications while awaiting HSCT.

Case 1

Baby N was a four-month-old baby girl, second born to nonconsanguineous parents. She had required hospital admission on three occasions, including a visit to the intensive care unit once for severe dehydration. An endoscopy revealed severe pancolitis with CMV inclusions, and her serum CMV DNA polymerase chain reaction (PCR) was also positive. The serum immunoglobulin levels revealed reduced IgG levels, and the lymphocyte subset analysis suggested severe combined immune deficiency. She was treated with intravenous ganciclovir and referred for HSCT. The CMV PCR and high-resolution computed tomography (HRCT) chest performed before HSCT were normal. She underwent a TCR alpha/beta depleted haploidentical stem cell transplantation from her father. Conditioning included fludarabine/treosulphan/ thiotepa//rabbit-anti thymocyte globulin, with stem cell dose of 15x10⁶/ kilogram recipient body weight. She had a stormy course post infusion with features of cytokine release syndrome requiring oxygen supplementation and inotropes and had grade 4 mucositis. She achieved neutrophil engraftment by D + 10, with 100% chimerism.

CMV reactivation was documented on D + 17 with copies up to 1839. She received ganciclovir and then cidofovir in view of increasing CMV copies. However, her CMV copies progressively increased to 300,000 when she developed respiratory distress. The respiratory symptoms progressed within two days requiring high ventilatory support and multiple inotropes. The repeat CMV copies were 17,00,000 on Day + 63. She was started on Foscarnet and needed increasing ventilator support and inotropes. She succumbed to refractory CMV disease around D + 70 post-HSCT (Fig. 1).

Case 2

Baby D, a two-year-old toddler girl, was apparently well till three months of age, when she developed ear discharge, loose stools, and fever, and had a skin rash which was treated as atopic dermatitis. She also suffered from frequent upper respiratory tract infections. In March 2022, her hemoglobin dropped to 2.6gm%, and she was diagnosed with autoimmune hemolytic anemia. She received packed red blood cell transfusions and steroids for the same. She continued to have recurrent viral infections including disseminated molluscum contagiosum and herpes zoster.

Pre-BMT viral monitoring was negative for all detectable viruses. She underwent a TCR alpha/beta depleted haploidentical stem cell transplantation from her father, with fludarabine/treosulphan/ thiotepa//rabbit-anti thymocyte globulin, for conditioning and PBSC dose of 12x10⁶/ kilogram recipient body weight. She had a stormy course during HSCT, with severe oral mucositis, persistent loose stools starting from Day 0, and multiple antihypertensive medications. She had an early engraftment on Day 10. She had adenoviral reactivation following engraftment with adenoviral copies of 30,73,000, and was started on weekly cidofovir (5milligram/kilogram). The viral copies continued to increase with copies of 18,769,600 (D + 17) and 85,395,600 (D + 24). On day + 46, she suddenly started developing abdominal distension along with altered gastric aspirate; she was given supportive care for the same; however, she succumbed to refractory adenovirus disease by Day + 48 post-HSCT.

Case 3

Baby K was apparently well till eight months of age when he developed recurrent skin infections, otitis media, and lower respiratory tract infection. He continued to have chronic diarrhea when stool for gastrointestinal panel revealed Giardiasis and Cryptosporidium parvum infection. He was treated for the same and was documented to be infection free prior to HSCT. The child underwent TCR alpha/beta depleted haploidentical HSCT from the father with thiotepa/treosulphan/fludarabine with CD34 dose of 15x10⁶/ kilogram recipient body weight. The child tolerated conditioning well. During HSCT, he did not encounter any significant complications and was documented to have complete chimerism. However, post 60 days following HSCT, he started developing progressively increasing copies of CMV, which remained refractory to ganciclovir, cidofovir and foscarnet. He succumbed to disseminated CMV infection by Day + 75 post-HSCT (Fig. 2).

Case 4 and 5

Master S, a four-year-old male child, on regular prophylaxis for the underlying DOCK8 deficiency, presented with obstruction of the nasal cavity, which was insidious in onset and gradually progressive. Parents also noticed swelling on the right side of the nose with the broadening of the bridge of the nasal cavity. CT of the paranasal sinuses, revealed a lesion arising from the nasopharynx with involvement of all paranasal sinus. Biopsy and immunohistochemistry confirmed a high-grade Burkitt`s lymphoma (Fig. 3). The child was categorized as Group B as per LMB-96 protocol, and chemotherapy was administered accordingly. He initially responded well and had symptomatic relief. However, after his last cycle of chemotherapy, he had severe headaches with a blurring of vision, and a CT brain was normal. The child later presented with sudden vision loss in the right eye with hearing impairment. An ophthalmological evaluation revealed retinal hemorrhage with a whitish, granular retina appearance suggestive of CMV retinitis versus tumor infiltrates. He later developed altered sensorium for which we performed a CSF analysis confirming the diagnosis of CMV encephalitis. Parents were counselled regarding guarded prognosis and opted for the best supportive care for the child. The child lost weight rapidly and ultimately succumbed to the illness.

Miss D, the elder sibling of Master S, was a 5-year-old female child with recurrent respiratory infections with significantly stunted growth and extensive bronchiectasis. The child was oxygen dependent and was never evaluated for any underlying cause. The child was evaluated after her sibling was diagnosed with DOCK 8 deficiency, when she was also found to harbour the same mutation. Parents refused HSCT, and hence she had been continued on prophylactic medications with the best supportive care. She was alive at last follow up and on home oxygen therapy.

Case 6 and 7

Two siblings, Master M, and Master S, presented at six years and eight years of age, respectively, with extensive skin impetigo. There were no other features suggestive of any infections or autoimmunity. However, the skin impetigo was extensive, and the elder sibling required prolonged antibiotics for Fournier’s gangrene, from which he has subsequently recovered. Whole exome sequencing and functional assays performed on both the children confirmed DOCK8 deficiency. On last follow up, both the children were on prophylactic antibiotics and monthly IVIG.

Case 8

Master K, was a seven-year-old male who presented initially at two months of age with recurrent otitis media, severe skin eczema, and extensive molluscum contagiosum. His whole exome sequencing confirmed DOCK8 deficiency. He had a matched unrelated donor HSCT with peripheral blood stem cells used as the source. He underwent myeloablative conditioning with fludarabine/busulphan and horse-antithymocyte globulin (ATG). The child engrafted and had CMV viral reactivation post-HSCT, which responded to ganciclovir. There was a significant resolution of the molluscum post-HSCT for the child. The child was four years post HSCT on last follow up and was growing well.

Case 9

Master K initially presented at three months of age with recurrent Klebsiella pneumoniae meningitis. He was diagnosed with DOCK8 deficiency and underwent matched sibling donor HSCT from his elder sister with reduced toxicity conditioning with fludarabine/treosulphan. The child tolerated conditioning well and had brisk engraftment. However, nine months post HSCT he developed mixed chimerism and secondary graft failure. Ultimately, he succumbed to septic shock four years post-transplant.

Out of the total five children who underwent HSCT in the cohort, 3/5 had haploidentical HSCT, and one child each had a matched family donor HSCT and one matched unrelated donor HSCT. The stem cell source used was PBSC in four children, while it was bone marrow in one child. The conditioning regimen was reduced intensity conditioning in two while myeloablative in the remaining three children. All children had brisk engraftment by around day 10. The outcomes of HSCT remained poor due to early and refractory viral reactivation, with 17,00,000 copies of cytomegalovirus in one child and 8,53,95,600 copies of adenovirus in another child. Graft rejection was also challenging, as seen in one patient who underwent a matched sibling donor transplantation and was doing well for two years. Mixed chimerism and late graft rejection lead to septic shock and death. The one child (1/5) who underwent a matched unrelated donor HSCT was doing well and was infection free. The overall survival rate in the cohort was 45.5% (4/9), while the survival rate was about 20% among children who underwent HSCT (1/5).

The study reports the disease manifestations and spectrum of infections in children with DOCK8 deficiency, with guarded survival and difficult natural course. Four of the nine (45%) children are alive, with significant morbidity due to end-organ damage because of recurrent infections. Survival following HSCT was 20% (1/5), with mortality due to refractory CMV and adenoviral reactivations following haploidentical HSCT. The youngest child in the cohort was two months old. Four out of the nine children (44%) presented during infancy, like previous studies reporting children with DOCK8 deficiency presenting at a young age, ranging from the first month to the early years of life [13].

Patients with DOCK8 deficiency are prone to viral infections, especially those affecting the skin. A few viral infections that these children are susceptible to include Varicella zoster, Molluscum contagiosum, Herpes simplex, and human papillomavirus [14, 15, 16]. Similarly, in our cohort, three of the nine children (33%) had severe, persistent, and extensive molluscum contagiosum, refractory to treatment. Of these, one child had a combination of herpes viral reactivation and molluscum contagiosum. Non-cutaneous viral infections are common including meningitis, encephalitis, keratitis, pneumonia, enteritis, and hepatitis. The viruses causing these infections include cytomegalovirus, Epstein-Barr virus, herpes simplex virus, and hepatitis A, B, and C viruses [7, 17, 18]. In the present cohort, one child presented with CMV colitis, proven by endoscopy biopsy at four months of age, and had received treatment with ganciclovir prior to transplant.

The spectrum of infections encountered can be variable, including both superficial and invasive bacterial infections. Patients often experience recurrent sinopulmonary infections that can ultimately lead to bronchiectasis [19]. In our cohort, three children had recurrent pneumonia, and one child is on home oxygen therapy because of extensive bronchiectasis.

Staphylococcus aureus-induced cutaneous skin infections are common in these children. This was evident from our cohort with two children, siblings presenting with extensive skin impetigo requiring a prolonged duration of antibiotics and are currently on long-term follow-up.

Unusual parasitic infections are also seen in children with DOCK8 deficiency, like cryptosporidium, Entamoeba histolytica, and Giardia lamblia, which can be damaging and difficult to treat, as seen in Hyper IgM syndrome [13, 19, 20]. Similarly, in our cohort, one child presented with multiple episodes of loose stools when evaluation suggested cryptosporidium and giardia infection in the stool.

DOCK8 deficient children suffer from severe autoimmune manifestations and are at an increased risk of malignancies compared to the general population [20, 21, 22]. The incidence of malignancy is up to 17% in these children [9]. Malignancies are usually virus-driven, like EBV-associated lymphoma or HPV-induced squamous cell carcinoma [10, 23]. The autoimmune manifestations include autoimmune hemolytic anemia, chorioretinitis, hypothyroidism, cytopenia, and vasculitis. In the present study, we treated one child with high-grade Burkitt`s lymphoma with chemotherapy, and he succumbed to CMV-induced encephalitis while awaiting HSCT. Another child who presented with significant autoimmune hemolytic anemia from infancy, refractory to multiple treatment modalities and had molluscum contagiosum. She succumbed to disseminated adenoviral infection post-HSCT.

Majority of the children with DOCK8 deficiency have stunting and failure to thrive, secondary to autoimmune associated malabsorption or infectious enteropathy [24]. One child in the cohort initially presented with persistent loose stools at four months of age and was diagnosed with cow milk protein allergy. Subsequently, when she had diarrhoea with severe dehydration requiring PICU admission, a colonoscopy was done, which revealed CMV inclusions, and she was later found to have DOCK8 deficiency.

DOCK8 deficiency can lead to significant morbidity and mortality. The overall probability of survival without definitive treatment with HSCT has declined from 87–37% at 10 and 30 years, respectively, according to Aydin SE et al [9]. The overall survival in the current cohort is 45%. Mortality in patients with DOCK8 deficiency is usually attributed to infections, malignancies, and sometimes unusually due to vasculitis. Causes of death in our cohort included malignancy in one child and infective complications in five children.

The definitive curative option for children with DOCK8 deficiency is haematopoietic stem cell transplantation. While treating children with DOCK8 deficiency, we need to screen for any infections/autoimmunity/malignancy, treat the same, and provide immunoprophylaxis. The total immunoglobulin levels remain normal in these children. However, the recommended standard of care is long-term IVIG prophylaxis because of impaired long-lived antibody responses [25].

The HSCT outcome in the cohort was dismal, with only one child alive out of the five children who underwent HSCT for the condition, i.e., 20% survival in the HSCT group. Most of the children in the cohort were diagnosed late and had multiple infections prior to their transplants which could have accounted for the high mortality rate in the cohort. All four children succumbed to diseases with disseminated cytomegalovirus in two, disseminated adenovirus in one child, and late septic shock in another child after secondary graft rejection. A study by Cuellar et al. demonstrates six patients with uniform myeloablative conditioning with either matched or unrelated donor HSCT who had successful transplants [26]. Another study conducted by Al-Herz et al. had eleven patients who underwent HSCT for DOCK8 deficiency, showing a successful post-transplant survival rate of around 91% despite significant pre-transplant morbidity in these patients [13].

Literature on DOCK8 deficiency and the disease manifestations is limited, with recent publications from India reporting diverse clinical features in these children [27]. Multicentre studies on DOCK8 deficiency and the disease spectrum are essential. Recent data has confirmed the role of HSCT in DOCK8 deficiency, with resolution of eczema and mollusca earlier than food allergies [28]. Maintaining complete chimerism with reduced toxicity conditioning has been shown to improve outcomes [29]. Haploidentical HSCT with post-transplant cyclophosphamide has also been shown to have an emerging role in these children [30]. Future studies are focussing on improving outcome with possible nanotechnology in HSCT for these disorders [31].

Our cohort depicted the diverse clinical presentation in these children from refractory viral infections, autoimmunity, malignancy, and skin manifestations. The various challenges encountered during management were the dramatic presentation, stubborn viral infections, inability to tolerate chemotherapy, and refractory autoimmunity. Early diagnosis of rare inborn errors of immunity like DOCK8 deficiency is still possible in limited resource settings with simple tools like eosinophilia, high IgE levels, and flow cytometry to evaluate DOCK8 expression. HSCT from a fully matched donor using reduced toxicity conditioning has the best outcome. HSCT using haploidentical donors poses significant challenges in these children with refractory viral infections, as evident from our cohort. Collaborative work and research are required to decide optimal care for these children to guide better treatment outcomes.

GVHD	Graft versus host disease
HSCT	Hematopoietic stem cell transplantation
DOCK8	Dedicator of cytokinesis 8
HPV	Human papilloma virus
CMV	Cytomegalovirus
MAC	Myeloablative conditioning
RIC	Reduced intensity conditioning
PBSC	Peripheral blood stem cells
MFD	Matched family donor
MUD	Matched unrelated donor
EBV	Epstein Barr virus
AR-HIES	Autosomal recessive Hyper IgE syndrome
IEI	Inborn errors of immunity
IVIG	Intravenous immunoglobulin
TCR	T cell receptor
HRCT	High resolution computed tomography
HPV	Human papilloma virus
PCR	Polymerase chain reaction

Acknowledgements: We would like to acknowledge the immense contribution of the stem cell pheresis team and nursing team in the management of these children

Funding: none

Conflicts of interest: none

Availability of data and material: not applicable

Author contributions: KG, RU, RR wrote the manuscript; SD, VM, AN helped with data collection; VVS helped with data analysis; IJ helped with editing; VK helped with proof reading

Ethics approval: obtained

Consent to participate: obtained

Consent for publication: obtained

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Emerging spectrum of DOCK8 deficiency in children and challenges associated with providing treatment: experience from a tertiary referral centre in India

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